The o;cial EFMC e-newsletter MedChemWatch

13 August 2011

71 EDITORIAL

72 PERSPECTIVE Knowledge Driven Drug Discovery goes Semantic

77 LAB PRESENTATION The Medicinal Chemistry Programme Group, University of Ljubljana, Faculty of Pharmacy, Slovenia

81 EFMC NEWS & EVENTS

82 NEWS FROM SOCIETIES

84 REPORT The II Edition of the SEQT Summer School on “Medicinal Chemistry in Drug Discovery: The Pharma Perspective”, Madrid, Spain

85 REPORT The XXXI Edition of the European School of Medicinal Chemistry , Urbino, Italy MedChemWatch no.13 August 2011 web: www.efmc.info/medchemwatch © 2011 by European Federation for Medicinal Chemistry

Editor Gabriele Costantino University of Parma, IT

Editorial Committee Erden Banoglu Gazi University, TR Lucija Peterlin Masic University of Ljubljana, SLO Leonardo Scapozza University of Geneve, CH Wolfgang Sippl University of Halle-Wittenberg, DE Sarah Skerratt Pfizer, Sandwich, UK

Design pupilla grafik web: www.pupilla.eu

Web Design Antalys Sprl web: www.antalys.be

European Federation for Medicinal Chemistry web: www.efmc.info e-mail: [email protected]

Executive Committee Gerhard F. Ecker President Hans-Ulrich Stilz President elect Koen Augustyns Secretary Rasmus P. Clausen Treasurer Hein Coolen Member Gabriele Costantino Member Javier Fernandez Member

The European Federation for Medicinal Chemistry (EFMC) is an independent association founded in 1970. Free from any political convictions, it represents 24 scientific organisations from 21 European countries and covers a geogra- phical area the size of the USA with a similar scientific population. Its objecti- ve is to advance the science of medicinal chemistry by promoting cooperation and encouraging strong links between the national adhering organisations in order to promote contacts and exchanges between medicinal chemists in Europe and around the World. EDITORIAL

Dear colleagues,

Modern drug discovery, similarly to other border disciplines, relies more and more on the availability, processing and mining of high quality data. Recent years have seen a growing availability of databases annotated with a variety of biological data, and for the first time academic researchers are beginning to have access to data generated under industry settings and standards. There is the risk, however, that the ability to generate data does not parallel the capacity to manage them, and, more importantly, to transform them into knowledge for medicinal chemists. In this context, we publish in this issue of MedChemWatch a Perspective article originally published in the 2011 EFMC yearbook. In this perspective, Niklas Blomberg, Gerhard Ecker, Richard Kidd, Barned Mons, and Byrn Williams-Jones comments on the opportunity that the semantic web technologies are offering to the medicinal chemistry community, and present the example of the Open Pharmacological Concept Triple Store (OpenPHACTS) towards the creation of an open pharmacological space.

Continuing our presentation of leading European labs, we present in this issue the laboratory of Prof. Danijel Kikelj, at the Faculty of Pharmacy of the University of Ljubljana, Slovenia,

Gloria Cristalli, director of the ESMEC-Urbino, the EFMC-accredited European School of Medicinal Chemistry, reports on the 31st edition of the School, which has been held on July, 3-8. The Second Summer School of Medicinal Chemistry, organized by the Spanish Society of Medicinal Chemistry has been granted this year as a EFMC event, and Maria Luz Lopez-Rodriguez and Javier Fernardez-Gadea report on the scientific outcome of the meeting.

As usual, you will find the columns on news from member societies and from the EC of the EFMC. Indeed, among the various and interesting events that will take place this year (and you will find the updated list in the ‘EFMC events’ section, as well as in the Meeting Calendar section of www.efmc.info) , the 4th edition of ASMC, which will be held in St. Petersburg, August 21-25, 2011

Gabriele Costantino, Editor of MedChemWatch

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Knowledge Driven Drug Discovery goes Semantic

by niklas blomberg, gerhard f. ecker, richard kidd, barend mons, bryn williams-jones*

While the availability of freely accessible information sources everyone, the chemoinformatics com- relevant to medicinal chemistry and drug discovery has grown over munity traditionally is closed and pro- the past few years, the knowledge management challenges of this prietary. Access to commercial databas- data have also grown enormously: how to get consistent answers, es of high quality crystal structures and chemical information requires licens- how to manage different interfaces, how to judge data quality, and es, as do most of the software packages how to combine and overlay the data to generate new knowledge. needed. Medium size and large sets of Open PHACTS (Open Pharmaological Concept Triple Store), bioactivity data per se are rare, as large a consortium of 22 partners, is poised to address this knowledge scale screening efforts have almost ex- management challenge with semantic web technology to accelerate clusively been performed in industrial laboratories. This has disconnected in- drug discovery. Here we describe the brief rationale, history and dustrial and academic drug discovery approach of the OpenPHACTS consortium with a final aim to create efforts and directed academia more an Open Pharmacological Space (OPS). towards method development. Fur- thermore, in silico models developed in academia have largely been restricted to Modern drug discovery research is secondary pharmacology to biomarker the small and scattered publicly avail- increasingly dependent on the avail- identification. able chemical space. ability, processing and mining of high quality data. Analysis and hypothesis Over the last 15 years industry has This setting changed drastically with generation for drug-discovery projects spend significant resources to integrate the NIH roadmap, which led to the requires careful assembly, overlay and public data and information sources creation of PubChem, a public available comparison of data from many sources. and align this with internal, proprie- depository of screening data. PubChem For example, expression profiles and tary data while the academic Medicinal currently comprises 31 million com- data from genome-wide association Chemistry research community suf- pounds, 73 million substances and studies (GWAS)1 need to be overlaid fered from lack of access to large data 490.000 bioassay results. Others like with gene and pathway identifiers and sets, especially those including curated DrugBank, ChemBank, IUPHAR, and reports on compounds in vitro and in bioactivity data. In contrast to data from ChEMBLdb followed soon and today vivo pharmacologyUtility of data-driven the bioinformatics world, where whole there is a panel of databases available research goes from virtual screening, organism genomes, protein sequences, which can be searched for compounds HTS analysis, via target fishing and and protein structures are available to and associated biological data. The cur-

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rent release of the ChEMBLdb contains data formats, and their focus is shifting identifier; another one is the IUPAC more than 2,4 million activities of ap- from data acquisition, to problem-solv- InChI which rapidly gains popularity prox. 623.000 compounds measured ing skills, knowledge management and and support. As data volumes increase against almost 7.200 targets.2 The lat- data integration.4 we would want to address increasingly est issue of the Nucleic acid research complex search questions and rapid an- database summary lists almost 140 in- Nevertheless, there is a real danger swers to questions such as “provide all dividual resources in the general field that the high capacity to generate more compounds which have been associated of molecular biology. However, there data will not be in sync with our ability with liver toxicity and list their interaction is still the urgent need for cleaning, to manage the data well enough and, profiles with the transporters expressed in improving and connecting these data more importantly, to transform these the liver” are becoming crucial for the to the public domain bioinformatics data into biological and biochemical success of drug discovery research pro- data, especially with respect to target knowledge. Data integration over mul- grams. Currently, answering such a validation, safety, efficacy and bioavail- tiple sources is not sufficient to under- broad question requires cumbersome ability. As an example, ChemSpider stand biology, but it is a prerequisite to parsings, reading and integration ef- was set up as a free access platform even start to understand the complex- forts. The ideal situation would be an for the aggregation, deposition and cu- ity of any process in living organisms. immediate answer to this question, ration of community chemistry data, As traditional medicinal chemistry re- with the full possibility to ‘drill down’ in which has collected almost 25 million search is embracing chemical biology the underlying information resources unique chemical structures linked out and make increased use of phenotypic for deeper investigation. to over 400 data sources. ChemSpider screening and high content biology for has addressed the issues around data SAR, the requirements on data-analysis The Concept Web Alliance (CWA), quality of chemical compound infor- and integration will increase.5 Unfor- formed in 209 and comprising over mation available across the public data tunately, this cumbersome and costly 90 participants from academia and sources by running automated clean- process is repeated across companies, the private sector worldwide, is a col- ing algorithms and providing wiki-like institutes and academic laboratories. laborative community seeking to ap- manual tools for commenting on and This represents a significant waste ply semantic concepts to deal with editing the aggregated compound in- and an opportunity cost and effectively the massive amounts of information formation. Another milestone was the slows down scientific progress and con- flooding the biological sciences and publication of the GSK ’Tres Cantos sequently biomedical intervention.6 (later) other scientific disciplines. Antimalarial Compound Set’, a set of Many participants are also participants 13 533 annotated compound structures The emerging semantic web technolo- or members of other related networks shown to inhibit Plasmodium growth.3 gies and approaches are one way to ad- and alliances, such as the W3C, the This for the first time allows academia dress this major bottleneck in contem- Pistoia Alliance and SageBionetworks, to get access to a large data set derived porary high throughput science. Sim- to name just a few. Collaboration of under industry settings and standards ply put, “semantic web approaches” these like-minded alliances is a stated and is likely to stimulate anti-malarial aims to establish unique identifiers for aim of CWA, which is built on the research through chemical biology and the concepts and entities within a given principles of Open Source, Open Ac- medicinal chemistry. domain to allow effective connections cess and Open Data. The rationale to be made between data sources. More for the CWA semantic web approach is Public access to large amounts of infor- ambitiously unique identifiers are not that classical data warehousing meth- mation, by means of the open access only assigned to “things” (e.g. a com- ods are no longer scalable to the size, policy for databases and papers, now pound) but also assigned to concepts spread and complexity of life science will assist academia to contribute in a such as “hydrolyses”, “is a”, etc (e.g datasets, information resources and meaningful manner to drug discovery. “NaCl is a salt”) to allow more advanced data analysis needs. These aims fit Medicinal Chemists are thus expected search and reasoning over large data- very well with the challenges already to familiarize themselves with a mul- sets. In the chemistry domain the CAS- identified in harnessing public data tiplicity of highly variable sources and number is an example of such a unique for drug discovery.

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A first step towards better global data In order to succeed and gain wide- and structured information in Re- integration and innovative ways to spread community adoption, this ap- source Description Framework (RDF) manage these data to produce mean- proach will need to go way beyond the assertions that together with prove- ingful information and finally knowl- current state of the art of tools in the nance data to form the basic building edge is obviously the interoperability of life sciences and semantic web domain. block of interoperability. The concept the various data and information sets. The transition from classical, hypoth- of RDF “triple”s (extracted simple as- Although standards are indispensible esis driven research towards systems sertions, also called nanopublications to this process, the discussions about approaches requires rigorous new by CWA) has already been adopted by standards can be lengthy and in fact methodology. A further key challenge a wide and rapidly expanding commu- may have an inherent potential side is that current data sources are largely nity and is being implemented both for effect of blocking the very process it incompatible with massive computa- bioinformatics and chemogenomics. aims to accelerate. The consequences tional approaches and the vast majority For instance, the Bio2RDF.org project of not agreeing to common standards of drug-discovery sources cannot easily aims to transform different sources are evident when looking on public bi- interoperate. Recently developed data of bioinformatics data into a distrib- oactivity data bases such as PubChem, and text mining approaches, improved uted platform for biological knowledge BindingDB, and DrugBank. All of data capture standards, and leveraging discovery.7 Initially, the authors fo- them host a broad range of pharmaco- semantic web technology open a first- cused on building a public database of logical activity data, mostly manually time-opportunity to achieve interoper- open-linked data with web-resolvable curated, which are accessible through ability through the semantic harmo- identifiers that provides information various web-based tools. However, the nization of data in key data sources. about named entities. This involved lack of common standards for repre- A priori data interoperability ‘at the the conversion of open data represent- sentation of these data makes it excru- source’ would therefore be a desired ed in a various formats to RDF-based ciatingly time consuming to exploit the long-term effect of this distributed ap- linked data with normalized names. information present. Nevertheless, in proach. Regarding questions around Bio2RDF entities also make reference a fully connected world where many long-term sustainability of available to other open linked data networks different teams are providing valuable, resources, recent studies in the scope thus facilitating traversal across infor- but specialist, data-sources top down of the ELIXIR project have shown that mation spaces. Bio2RDF is currently approaches as e.g. previously enforced out of 531 databases surveyed, 63 were indexing around 5 billion triples, and by IUPAC for chemical nomenclature, either not online anymore or had not is built with the open source Virtuoso will most likely fail in the biomedical been updated since 2005 and, for a database. However, currently the re- domain. As an example, the CWA has further 78, the update status was un- dundancy problem is not yet handled adopted the approach of ‘bottom up clear. More importantly, less than 10% in Bio2RDF and in the linked open standard setting by best practices’. Rec- of the biomolecular resources surveyed “data-cloud” in general. One step fur- ognizing that the power of standards indicated that they had multi-annual ther is the Chem2Bio2RDF initiative, lies in their widespread adoption the funding secured. The data resource which comprises a repository aggregat- CWA firmly believe that the only long- landscape is therefore very fragile and ing data from multiple chemogenomic term sustainable model for a scientific a large and influential consortium in- data sources that is cross-linked to Bi- system to support global computation- volving academic as well as industrial o2RDF. Chem2Bio2RDF also includes al biology approaches as needed is full drug-discovery partners can play an a tool to facilitate query generation as openness around the core semantic important role in capturing the most well as a set of extended functions to components, vocabularies and inter- important ‘assertional content’ globally address specific chemical/biological faces. However, this does not preclude in a stable, interoperable and sustain- search needs. Potential usefulness in the exposure and the delivery of pro- able format. specific examples of polypharmacol- prietary content, nor does it preclude ogy, multiple pathway inhibition and value-added closed-source or commer- The semantic approach, is based on adverse drug reaction–pathway map- cial services delivered on top of this the extraction and encoding of free- ping has been demonstrated.8 Another system. text, table, image, molecular sequence very valuable source recently launched

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is ChemProt (www.cbs.dtu.dk/ser- benefit of both pharma and academic of other Knowledge Management pro- vices/ChemProt/), a disease chemical drug-discovery communities. jects in IMI and a wider community biology database, which is based on Open PHACTS, the winning consorti- of like-minded partners it is likely that a compilation of multiple chemical– um, will concentrate on a semantic web already in 2011 the approach taken by protein annotation resources, as well approach to develop an open source, Open PHACTS will be actively fol- as disease-associated protein–protein open standards and open access in- lowed, co-developed and implemented interactions (PPIs).9 ChemProt com- novation platform (OPS). The Open by close to 100 partners world-wide. prises more than 700.000 unique PHACTS project will be one of the first Any partner with an interest and an chemicals with biological annotation international attempts to create a reli- ability to contribute data, software or for 30.578 proteins, leading to more able and scalable system, a common expertise is principally considered as than 2 million chemical–protein in- product beyond collective prototyping. an ‘associated partner’. teractions, which were integrated in a OPS aims to deliver a sustainable, reli- quality scored human PPI network of able web based environment through Dissemination and community en- 428.429 interactions. ChemProt can proven agile software engineering gagement will also utilize the manifold assist in the in silico evaluation of en- models. OPS will comprise data, vo- channels EFMC and RSC can provide. vironmental chemicals, natural prod- cabularies and infrastructure needed A large and influential consortium ucts and approved drugs, as well as to accelerate drug-oriented research. like this, involving academic groups, the selection of new compounds based This semantic integration hub will learned societies, as well as industrial on their activity profile against most address key bottlenecks in small mol- drug-discovery partners collaborat- known biological targets, including ecule drug discovery: disparate infor- ing in the context of OPS is likely to those related to adverse drug events. mation sources, lack of standards and increasingly drive researchers around Nevertheless, the increasing availabil- shared concept identifiers, guided by the globe to capture and distribute ity of linked data sources also requires well defined research questions assem- data and information in a semantically innovative browsing and navigation bled from participating drug discovery interoperable and computer readable tools, such as iPHACE (cgl.imim.es/ teams. Workflows for data capture, format, as their data will ‹connect› and iphace/).10 iPHACE represents an in- processing, interoperability, visualiza- ‹mean› more from the onset. We there- tegrative web-based tool to navigate in tion, and chemogenomics will be de- fore emphasize that - if successful and the pharmacological space defined by veloped to create a comprehensive sustainable – the OPS project is likely small molecule drugs contained in the Systems Chemical Biology Analysis to significantly contribute to more suc- IUPHAR-DB, with additional interac- Network. Security issues around pro- cessful and cost-effective development tions present in PDSP. Extending be- prietary data, shared via the CWA na- of drugs and vaccines in human and yond traditional querying and filtering nopublication system and accessible animal health, as well as in nutrition tools, iPHACE offers a means to ex- for safe querying and reasoning will be and personal genomics. Turning data tract knowledge from the target profile properly addressed with expert trusted into knowledge is the cornerstone of of drugs as well as from the drug pro- parties. The core Open PHACTS con- successful drug discovery, but is the file of protein targets. sortium comprises 14 European core core business of science in general. academic and SME partners as well A future driven by the open sharing Open Pharmacological Space as 8 EFPIA members, with leading of data, tools, services and workflows In light of all these developments and experts in the fields of data mining, benefits the whole scientific commu- in order to foster public-private part- annotation, small molecule data stor- nity. nership the Innovative Medicines Ini- age and manipulation, target related tiative launched a call for development bioinformatics, RDF-type information of an Open Pharmacological Space to handling, massive in silico reasoning establish a set of practical standards and chemical biology. Noteworthy, for the major public drug discovery re- Open PHACTS is not only open in sources and to implement these stand- terms of data but also in terms of the ards in a public infrastructure to the consortium itself. With the alignment

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References:

1 Johnson AD, O’Donnell CJ. An Open Access Database of Genome- wide Association Results. BMC Medical Genetics 2009, 10:6. 2 Bender A. Compound bioactivities go public. Nature Chem Biol 2010, 6, 309 3 Gamo F-J, Sanz LM, Vidal J, de Cozar C, Alvarez E, Lavandera J-L, Vanderwall DE, Green DVS, Kumar V, Hasan S, Brown JR, Peishoff CE, Cardon LR, Garcia-Bustos JF. Thousands of chemical starting points for antimalarial lead identification. Nature 2010, 465, 305-310. 4 Broccatelli F, Carosati E, Cruciani G, Oprea TI. Tranporter-mediated efflux influences CNS side effects: ABCB1, from antitargets to target. Mol Inf 2010, 29, 16-26. 5 Hoffmann T, Bishop C. The future of discovery chemistry: quo vadis? Academic to industrial – the maturation of medicinal chemistry to chemical biology. Drug Discovery Today 2010, 15, 260-264 6 Barnes MR, Harland L, Foord SM, Hall MD, Dix I, Thomas S, Williams- Jones BI, Brouwer C. Lowering industry firewalls_pre-competitive informatics initiatives in drug discovery. Nature Reviews Drug Discovery 2009, 8, 701-708 7 Belleau, F, Nolin, M, Tourigny, N, Rigault, P, & Morissette, J. Bio2RDF: Towards a mashup to build bioinformatics knowledge systems Journal of Biomedical Informatics 2008, 41, 706-716. 8 Chen, B, Dong X, Jiao D, Wang H, Zhu Q, Ding Y, Wild DJ. Chem2Bio2RDF: a semantic framework for linking and data mining chemogenomic and systems chemical biology data. BMC Bioinformatics 2010, 11, 255. 9 Tabourou O, Nielsen SK, Audouze K, Weinhold N, Edsgard D, Roque FS, Kouskoumvekaki I, Bora A, Curpan R, Jensen TS, Brunak S, Oprea TI.. Nucleic Acid Res 2010, published online Oct 8. 10 Garcia-Serna R, Ursu O, Oprea TI, Mestres J. iPHACE: integrative navigation in pharmacological space. Bioinformatics 2010, 26, 985-986.

*Niklas Blomberg DECS Computational Chemistry,AstraZeneca R&D Mölndal, Sweden Gerhard F. Ecker Dept. Medicinal Chemistry, Univ. Vienna, Austria Richard Kidd Royal Society of Chemistry, Cambridge, United Kingdom Barend Mons Netherlands Bioinformatics Center and Leiden University Medical Center, Leiden, The Netherlands Bryn Williams-Jones Pfizer Worldwide R&D, Sandwich Research,United Kingdom

MCW 76 LAB PRESENTATION

The Medicinal Chemistry Programme Group University of Ljubljana, Faculty of Pharmacy, Slovenia

danijel kikelj

Mission of the programme group Medicinal Chemistry at the hibitor for later preclinical development (http://cordis.eu- University of Ljubljana - Faculty of Pharmacy (http://www. ropa.eu/home_en.html). ffa.uni-lj.si/en.html)), leaded by Danijel Kikelj and compris- ing several research labs, is a high-quality research in medic- The interdisciplinary conceived research programme Medici- inal chemistry directed towards discovery of novel biological- nal Chemistry which is based on a uniform concept which ly active compounds for human health. In order to fulfil this comprises (i) understanding the biomolecular basis of dis- mission, the programme team is engaged in design, synthe- ease and (ii) knowing the 3D structure of biological macro- sis and biological evaluation of bioactive compounds, in de- molecules (enzymes, receptors) involved in particular dis- velopment of new approaches to drug design and synthesis, ease, is focusing on (a) rational design and discovery of drug and in development of novel molecular tools for studying the molecules exerting their action on validated biological tar- action of bioactive compounds on molecular level. gets, (b) their synthesis and (c) biological evaluation aiming at discovery of innovative medicines with antimicrobial and The programme group, financed by grants from the Slo- antiviral, antithrombotic and antitumour activity. A new par- venian Research Agency (http://www.arrs.gov.si/sl/), adigm of designed multiple ligands targeting two or more is becoming increasingly engaged in EU projects. The biological macromolecules is being applied as an innovative Framework 6 project INTAFAR (Inhibition of New Targets approach to the design of antithrombotic, antibacterial and for Fighting Antibiotic Resistance), aiming at better under- antitumour drugs. A constituent part of the programme is standing of the physiology and biochemistry of bacterial genomic research which is concentrating on studying influ- cell morphogenesis and peptidoglycan biosynthesis was ence of compounds, designed and prepared following the successfully finished in 2010 (http://www.eur-intafar.eu/). outlined concepts, on expression and interactions of proteins In 2010 the programme group started with a 4-year FP7 EU in the cell. The aims of this strategy are new innovative bio- collaborative project Exploring Marine Resources for Bioactive active compounds with a potential to be developed to drugs Compounds: From Discovery to Sustainable Production and and understanding of their complex action on protein net- Industrial Applications (MAREX) in which marine bioactive work in the cell. compounds are being used as leads for drug design (http:// With the aim of achieving therapeutical benefit in bacte- www.marex.fi/). In 2011 the programme team started with rial, viral, thrombotic and cancer diseases, our research is the FP7 EU project ORCHID (Open Collaborative Model for concentrated on (i) bacterial enzymes involved in intracellular Tuberculosis Lead Optimization) which will encompass the steps of peptidoglycan biosynthesis and enzymes which are anti- parallel progression of the three anti-tubercular compound tubercular targets (ii) enzymes involved in the process of blood co- families through lead optimization and MoA studies for agulation and other serine proteases involved in apoptosis (iii) en- whole cell inhibitors and the optimization of an InhA in- zymes involved in metabolism of steroid hormones, (iv) fibrinogen

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and vitronectin receptors and (v) receptor DC-SIGN of dendritic cells. The dogma of achieving the possibly highest selectivity on particular target still prevailing drug design is being criti- cally confronted with emerging concept of designed multiple ligands which achieve better therapeutic effect by simultane- ous modulation of several target macromolecules. Combina- tion of enzyme inhibitory action and receptor modulation activity in a single molecule with the aim of achieving thera- peutical benefit represents an outstanding challenge for the research programme. The first successful steps towards Figure 1. X-ray binding mode of dual inhibitor (IC50 S. aureus MurD = 8,2 integration of receptor antagonist and enzyme inhibitor in mM; IC50 S. aureus MurE = 17,5 mM) possessing antibacterial activity (MIC S. aureus and MRSA = 8 mg/mL) (in magenta) in the active site of MurD (PDB the same molecule, still being in the initial stage worldwide, ID code: 2Y1O) and GOLD-calculated conformation of the same inhibitor in has been already done by our group in antithrombotic com- MurE model active site (in magenta). Hydrogen bonds between dual inhibitor pounds and we are striving to develop this concept into an and MurD and MurE active site residues or crystal water molecules (in red) are presented as dashed lines (Tomašić et al., unpublished results). established strategy also in other therapeutic fields. For ra- tional design of drugs targeting particular biological macro- molecules we are using molecular modeling tools and devel- Selected recent publications: oping a concept of mimicking biologically active peptides, 1 Tomašić T, Zidar N, Šink R, Kovać A, Blanot D, Contreras-Martel C, sugars and lipids with peptidomimetics, glycomimetics and Dessen A, Müller-Premru M, Zega A, Gobec S, Kikelj D, Peterlin-Mašić lipidomimetics, which still remains a leading strategy in L. Structure-based design of a new series of D-Glutamic acid-based drug design starting from natural lead compounds. inhibitors of bacterial UDP-N-acetylmuramoyl-L-alanine:D-glutamate ligase (MurD). J Med Chem 2011, 54, 4600-4610. 2 Turk S, Verlaine O, Gerards T, Živec M, Humljan J, Sosić I, Amoroso A, Based on the presented uniform concept, the programme Zervosen A, Luxen A, Joris B, Gobec S. New noncovalent inhibitors of comprises the following main research topics: penicillin-binding proteins from penicillin-resistant bacteria. PLoS one 2011, 6, e19418. Tomašić T, Kovać A, Klebe G, Blanot D, Gobec S, Kikelj D, Peterlin-Mašić L. Virtual screening for potential inhibitors of bacterial MurC and MurD Inhibitors of peptidoglycan biosynthesis ligases. J Mol Model 2011, doi: 10.1007/s00894-011-1139-8. 3 Sosić I, Barreteau H, Simćić M, Šink R, Cesar J, Zega A, Golić, Grdadolnik The biosynthesis of peptidoglycan is a complex process S, Contreras Martel C, Dessen A, Amoroso A, Joris B, Blanot D, Gobec which is carried out in three distinct cell phases (cytoplas- S. Second-generation sulfonamide inhibitors of d-glutamic acid-adding mic, membrane and periplasmic) and which involves over enzyme: activity optimisation with conformationally rigid analogues of d-glutamic acid. Eur J Med Chem 2011, 46, 2880-2894. 20 enzymes. Due to the essential character of peptidogly- 4 Zidar N, Tomašić T, Šink R, Škedelj V, Kovać A, Turk S, Patin D, Blanot can, action of specific inhibitors of its biosynthesis during D, Contreras Martel C, Dessen, A, Müller-Premru M, Zega A, Gobec S, bacterial growth rapidly leads to the destructuration of the Peterlin-Mašić L, Kikelj D. Discovery of novel 5-benzylidenerhodanine and 5-benzylidenethiazolidine-2,4-dione inhibitors of MurD ligase. J Med envelope and to cell lysis. The numerous enzymes involved Chem 2010, 53, 6584-6594. in this biosynthetic pathway thus constitute potential tar- 5 Tomašić, T, Zidar N, Kovać A, Turk S, Simćić M, Blanot D, Müller-Premru gets for the search for new antibacterial drugs. Several in- M, Filipić M, Golić Grdadolnik S, Zega A, Anderluh M, Gobec S, Kikelj D, Peterlin-Mašić L. 5-Benzylidenethiazolidin-4-ones as multitarget hibitors of biosynthesis of the peptide part of peptidoglycan, inhibitors of bacterial Mur ligases. ChemMedChem 2010, 5, 286-295. catalyzed by Mur ligases (MurC, MurD, MurE and MurF) as 6 Humljan J, Kotnik M, Contreras-Martel C, Blanot D, Urleb U, Dessen well as D-alanine-D-alanine ligase (Ddl), have recently been A, Šolmajer T, Gobec S. Novel naphthalene-N-sulfonyl-d-glutamic acid derivatives as inhibitors of MurD, a key peptidoglycan biosynthesis designed and synthesized by our programme group (Figure enzyme. J Med Chem 2008, 51, 7486-7494. 1). We try to apply the multiple inhibition concept to ATP-de- pendant Mur enzymes with a hope that a succesful inhibition of ATP binding to the ATP-binding site could, if a problem Antagonists of receptor DC-SIGN as potential antibacterial of selectivity against other ATP-dependant enzymes such as and antiviral compounds human kinases would be successfully solved, lead to effec- DC-SIGN (Dendritic Cell-Specific ICAM-3 Grabbing Non- tive universal chemoterapeutics. integrin) is a C-type lectin implicated in the recognition of pathogens and in some of the earliest stages of the infection

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process. Certain pathogens exploit DC-SIGN in order to bind Recent publicartions: immune system cells, but circumvent the processes of inter- 1 Starčevič Š, Brožič P, Turk S, Cesar J, Lanišnik-Rižner T, Gobec S. nalization and degradation. DC-SIGN is thus used as a Tro- Synthesis and biological evaluation of (6- and 7-phenyl) coumarin jan horse to invade lymphocytes T CD4+, which is the main derivatives as selective nonsteroidal inhibitors of 17beta-hydroxysteroid HIV invading mechanism. Recently we have designed, syn- dehydrogenase type 1. J Med Chem 2011, 54, 248-261. 2 Brunskole Švegelj M, Turk S, Brus B, Stojan J, Lanišnik-Rižner T, Gobec thesized and biologically evaluated several families of DC- S. Novel inhibitors of trihydroxynaphthalene reductase with antifungal SIGN antagonists and developed an assay that measures in- activity identified by ligand-based and structure-based virtual screening. hibition of human dendritic cell adhesion on mannan-coated J Chem Inf Mod 2011, doi: 10.1021/ci2001499. 3 Starčevič Š, Kocbek P, Hribar G, Lanišnik-Rižner T, Gobec S. Biochemical microtiter plates, suitable for screening a large number of and biological evaluation of novel potent coumarin inhibitor of 17ß-HSD compounds, determination of inhibitory constants (IC50) type 1. Chem Biol Interact 2011, doi: 10.1016/j.cbi.2011.01.002, and fast discovery of new DC-SIGN antagonists. 4 Brožič P, Turk S, Lanišnik-Rižner T, Gobec S. Discovery of new inhibitors of aldo-keto reductase 1C1 by structure-based virtual screening. Mol. Cell. Endocrinol. 2009, 301, 245-250. Recent publications: Coagulation enzymes inhibitors and modulators of fibrino- 1 Obermajer N, Sattin S, Colombo C, Bruno M, Švajger U, Anderluh M, BernardI A. Design, synthesis and activity evaluation of mannose-based gen receptor as novel antithrombotic compounds with dual DC-SIGN antagonists. Molecular Diversity 2011, 15, 347-360. action 2 Obermajer N, Švajger U, Jeras M, Sattin S, Bernardi A, Anderluh M. An In order to achieve a synergistic antithrombotic effect, si- assay for functional dendritic cell-specific ICAM-3-grabbing nonintegrin (DC-SIGN) inhibitors of human dendritic cell adhesion. Anal Biochem multaneous application of anticoagulant and antiaggrega- 2010, 406, 222-229. tory drugs (e.g. thrombin inhibitors and fibrinogen receptor 3 Timpano G, Tabarani G, Anderluh M, Invernizzi D, Vasile F, Potenza antagonists) is frequently applied in clinical practice. Com- D, Nieto, Pedro M, Rojo J, Fieschi F, Bernardi A. Synthesis of novel DC-SIGN ligands with an [alpha]-fucosylamide anchor. ChemBioChem plementary structures of pharmacophores D-Phe-Pro-Arg of 2008, 9, 1921-1930. thrombin inhibitors and Arg-Gly-Asp of fibrinogen receptor antagonists inspired us to merge both pharmacophores in a low-molecular weight peptidomimetic compounds which Inhibitors of steroid hormone metabolism as potential anti- inhibit thrombin and act as antagonist of fibrinogen recep- tumour drugs tor, thus displaying anticoagulant and antiaggregatory activ- Steroid hormones play an important role in the aetiology ity. Optimization of a class of compounds afforded dual an- of hormone-dependent diseases, such as breast, prostate tithrombotic compounds possessing a well balanced activity and endometrial cancer, disorders of reproduction, and on both (Figure 2). The best classes of antithrombotic leads neuronal diseases. The occupancy of the steroid hormone with dual function were found to possess antioxidative and receptors is regulated mainly by hydroxysteroid dehydroge- radical scavenging activity which synergistically contributes nases, which convert steroids at positions 3, 11, 17 and 20 of to their antithrombotic potential. the steroid core, thereby acting as molecular switches. The 17β-hydroxysteroid dehydrogenases (17β-HSDs) modulate Selected publications: the biological potencies of estrogens and androgens by con- 1 Ilić M, Kontogiorgos C, Hadjipavlou-Litina D, Ilaš J, Kikelj D. Thrombin verting inactive 17-keto-steroids into their active 17β-hydroxy- inhibitors with lipid peroxidation and lipoxygenase inhibitory activities. forms (such as estradiol, testosterone and dihydrotestoster- Bioorg Me. Chem Lett 2011, doi: 10.1016/j.bmcl.2011.06.089. one), or vice versa. These enzymes play a key role in hor- 2 Ilaš J, Jakopin Ž, Borštnar T, Stegnar M, Kikelj D. 3,4-Dihydro-2H-1,4- benzoxazine derivatives combining thrombin inhibitory and glycoprotein monal regulation and function in the human and represent IIb/IIIa receptor antagonistic activity as a novel class of antithrombotic emerging therapeutic target for the control of estrogene- and compounds with dual function. J Med Chem 2008, 51, 5617-5629, androgene-sensitive cancers. Recently we have discovered 3 Ilaš J, Tomašić T, Kikelj D. Novel potent and selective thrombin inhibitors based on a central 1,4-benzoxazin-3(4H)-one scaffold. J Med Chem 2008, that simple coumarines prepared by Suzuki-Miyaura cross 51, 2863-2867. coupling reaction significantly inhibit 17β-HSD1 in a recom- 4 Štefanić P, Anderluh M, Ilaš J, Mravljak J, Sollner Dolenc M, Stegnar M, binant enzyme assay with high selectivity over 17β-HSD2. Kikelj D. Toward a novel class of antithrombotic compounds with dual function. Discovery of 1,4-benzoxazin-3(4H)-one derivatives possessing The best inhibitors in series were 7-phenyl-3-acetyl coumarin thrombin inhibitory and fibrinogen receptor antagonistic activities. J Med derivatives with the most potent compound having IC50 val- Chem 2005, 48, 3110-3113. ue of 268 nM and good selectivity over 17β-HSD2 receptors.

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Figure 3. Nitroxide-fluorophore double probes: a potential tool for studying membrane heterogeneity by ESR and fluorescence.

Selected publications:

1 Pajk S, Garvas M, Štrancar J, Pečar S. Nitroxide-fluorophore double probes: a potential tool for studying membrane heterogeneity by ESR and fluorescence. Org Biomol Chem 2011, 9, 4150-4159. 2 Humar M, Ravnik M, Pajk S, Muševič, I. Electrically tunable liquid crystal optical microresonators. Nature Photonics 2009, 3, 595-600. Pajk S, Pečar S. Synthesis of novel amphiphilic spin probes with the paramagnetic doxyl group in the polar region. Tetrahedron 2009, 65, 659- Figure 2. Dual antithrombotic compounds (R)-18c and (R)-18d docked in the 665. active site of thrombin (top) and GPIIb/IIIa binding site (below). 3 Mravljak J, Pečar S. A new glucosamine-containing amphiphilic spin probe. Tetrahedron Lett 2009, 50, 567-569.

Nitroxide-fluorophore double probes Study of the transmembrane signal transduction mecha- Group Members nism with non-destructive spectroscopic methods [electron Danijel Kikelj, Stanislav Gobec, Marija Sollner Dolenc, Aleš paramagnetic resonance (EPR) and fluorescence spectros- Obreza, Lucija Peterlin Mašič, Anamarija Zega, Marko An- copy/microscopy (FS)] is connected with progress in appro- derluh, Jožko Cesar, Janez Ilaš, Janez Mravljak, Matej Sova, priate molecular tools – spin-labels, fluorescence-labels and Rok Frlan, Žiga Jakopin, Matej Živec, Samo Turk, Nace Zidar, dual probes. To study extra cellular surfaces, cell interactions Tihomir Tomašič, Roman Šink, Stane Pajk, Irena Mlinarič with its surrounding and influence of cholesterol oxidized Raščan, Nataša Karas Kuželički and Damjan Janeš. products on membrane domain structure, we try to develop For a complete bibliography of the programme group in labelled glycomimetics and lipidomimetics which will ena- the last 3 years see http://izumbib.izum.si/bibliografije/ ble efficient exploitation of all possibilities of non-destructive P20110721144750-P1-0208.html spectroscopic methods like EPR and FS. A further focus of our research is on design and synthesis of labelled glycomi- metics and lipidomimetics with preserved biological activ- Contact: ity of non-labelled parent molecule. A special attention is Prof. Dr. Danijel Kikelj focused on design and synthesis of dual labelled molecular University of Ljubljana, Faculty of Pharmacy probes that combine paramagnetic nitroxide group and fluo- Aškerčeva 7, 1000 Ljubljana, Slovenia rophore. We expect that dual probes will enable simultane- Phone: +386-1-4769561 ous application of two non-destructive spectroscopic (EPR, Fax: +386-1-4258031 FS) techniques and thus make possible more profound un- E-mail: [email protected] derstanding of membrane processes.

MCW 80 EFMC NEWS & EVENTS by nele coulier and koen augustyns

EFMC is very proud to announce the Diseases” at PharmSciFair 2011, held in Annual One Day Meeting on Medicinal launch of its brand new website! A mod- Prague on June 13-17. EFMC was highly Chemistry At SRC & KVCV: “Drug ern design and structure together with pleased with the quality of the contribu- Design Against Emerging Targets: an interesting, up to date content makes tions from Simon Croft, Maria Laura Bo- Opportunities and Challenges” the site interesting and attractive for the lognesi, Reto Brun, Oludotun A. Phililps, November 25, 2011, Ghent (B) medchem community. We invite you to Franz Bucar and Anthony Williams. http://www.ldorganisation.com have a look at www.efmc.info, to find out more on the numerous activities of At the EFMC Council meeting, held on EFMC Sponsored Session on Oncology EFMC. We encourage any feedback from June 19 in Stockholm on occasion of the at the AFMC Meeting 2011 users of the site. Please feel free to email Frontiers in Medicinal Chemistry, the Nov. 29-Dec. 2, 2011, Tokyo (J) the Administrative Secretariat (admin- Council elected Phil Jones (UK) as new http://www.aimecs11.org/ [email protected]) with your recom- member of the Executive Committee. mendations. From January 1, 2012 on Phil Jones will 30th Noordwijkerhout-Camerino- replace Javier Fernandez (Spain). Cyprus Symposium Join us on LinkedIn! Become member May 13-17, 2012, Amsterdam (NL) of the EFMC LinkedIn group and stay EFMC ORGANISED EVENTS [email protected] updated on EFMC activities. As the group becomes populated, this will cre- 4th International Symposium on EFMC Sponsored Session at the 4th ate a unique online forum for medicinal Advances in Synthetic and Medicinal EuCheMS Chemistry Congress chemistry. Chemistry August 26-30, 2012 August 21-25, 2011, St-Petersburg (RUS) Prague (CZ) The third edition of “Frontiers in Me- http://www.asmc11.org http://www.euchems-prague2012.cz/ dicinal Chemistry – Emerging Targets, Novel Candidates and Innovative Strate- 4th EFMC Short Course on Medicinal gies” has been organised on June 19-21 Chemistry – Safety and Attrition EFMC SPONSORED SCHOOLS in Stockholm together with the Swedish December 7-9, 2011, Oegstgeest (NL) Academy of Pharmaceutical Sciences http://www.ldorganisation.com 6th Summer School on Drug Design and the Medicinal Chemistry Division September 11-16, 2011, Vienna (A) of the American Chemical Society. Fol- EFMC SPONSORED EVENTS http://summerschool.europin.at lowing the spirit of this series, it brought together top quality speakers from the 4th BBBB International Conference on Summer School on Pharmaceutical Scandinavian region and from the US, Pharmaceutical Sciences Analysis (SSPA) and attracted more than 250 partici- September 29-October 1, 2011 September 19-21, 2011, Pavia (I) pants. A report of the meeting is avail- Bled (SLO) http://chifar.unipv.it/sspa2011/ able under “EFMC events”. http://www.bbbb-eufeps.org/ 20th LACDR School on Medicinal Together with Maurizio Botta and Ulrike 29th Cyprus-Noordwijkerhout- Chemistry Holzgrabe, Gerhard Ecker organised two Camerino Symposium October 25-28, 2011 EFMC-sponsored sessions on “Innova- October 2-7, 2011, Limassol (CY) Oegstgeest (near Leiden) (NL) tive Strategies to Combat Neglected http://www.quintessence.com.cy http://medchem.lacdr.gorlaeus.net/node/3039

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2nd Edition of the SEQT Research at Janssen Spain) and Prof. the case studies, two poster sessions Summer School on Gabriele Costantino (EC member, rep- gave the opportunity to the attendants resenting EFMC). Then, during three to present their works and to discuss “Medicinal Chemistry intense days, an enthusiastic teaching with the teachers and the senior par- in Drug Discovery: team, composed by Kristof van Emelen ticipants the most significant aspects of The Pharma Perspective” (Janssen), Mark Bunnage (Pfizer), Jordi their research. In addition, the teachers Gràcia (Almirall), Víctor Rubio (Faes together with the organizing and scien- by maría luz lópez rodríguez Farma), Rob Young (GlaxoSmithKline) tific committee selected 15 posters to silvia ortega gutiérrez and José Cid (Janssen) handled different be presented as short oral communica- javier fernández gadea case studies in a very interactive man- tions by the young researchers. These ner fostering the discussion among the sessions were also highly valued by the participants, organized during all the participants. REPORT school in several work-teams. The ses- The venue, conveniently located close The second edition of the SEQT Summer sions covered a number of topics deal- to Madrid (in the pleasant village of San School on “Medicinal Chemistry in Drug ing with the different stages of modern Lorenzo de El Escorial), was Euroforum Discovery: The Pharma Perspective” has research and development in industry. Felipe II. The place was originally built become a major success. It took place Among them, the speakers considered as a luxury hotel and situated in a privi- in San Lorenzo de El Escorial (Madrid, essential aspects about target selection leged residential area, among the forest Spain) on 26-29 June, 2011. This second and hit design and development, with and half-way up the Abantos massif. To- edition of the Summer School, an event a special emphasis on the pharmacoki- day it has been turned into the modern sponsored by the European Federation netic properties. Also, the importance of and comfortable Executive Development of Medicinal Chemistry (EFMC), was the scale-up and production processes Centre. organized by the Spanish Society of Me- was also highlighted. All in sum, the motivating scientific en- dicinal Chemistry (SEQT) and Janssen The participants rated both the teach- vironment during the sessions and the with the aim of approaching the phar- ers and the information they provided friendly and informal atmosphere, to- ma industry to young researchers, both very high (an average of 4.65 out of gether with the careful organization and graduate students and post-doctoral as- 5.00). The open interactive atmosphere the availability of the teachers through- sociates working in the chemistry and was deeply appreciated. The inclusion out the school, were highly appreciated health sciences related fields. of questions during the cases studies by the participants who praised the During the three days of the school, 65 as well as sessions with questions and school as highly productive, interesting participants coming from seven differ- problems based on the preceding talks and formative event. ent countries around the world gathered was extremely successful. In addition to together in the first-class facilities of Eu- roforum-Felipe II. The attendants (30% of whom were from the industry and the remaining 70% came from academia) had the opportunity to learn about the latest research trends in pharmaceutical drug discovery and development illus- trated through real case studies led by an exceptional panel of industry experts currently working at international phar- ma industries. The School started on with the open- ing session led by Prof. María L. López- Rodríguez (SEQT President), Dr. Javier Fernández-Gadea (Director of Basic

MCW 82 MEDCHEMWATCH NO.13 AUGUST 2011

The XXXI Edition of and Gian Maria Rossolini (University of concept of generating compounds that the European School Siena, I) introducing the misuse of an- alter receptor function from the inside tibiotics and the rise of bacterial resist- (i) of the cell by regulating intracellular of Medicinal Chemistry ance as a major driver of unmet clinical (i) trafficking; in other words, on the (ESMEC) has successfully needs. In fact, despite the successes of discovery of i‐agonists and i‐antago- been held in Urbino (Italy) the antibacterial chemotherapy, resist- nists, where the “i” refers to inside and ance to several antibiotic classes began intracellular regulation. The second by gloria cristalli to emerge in Gram-positive bacteria speaker, Domenico Raimondo (Univer- in the United States during the 1990s. sity “La Sapienza”, Roma, I), presented The emergence of multidrug-resistant computational approaches for studying REPORT strains of S. pneumoniae, Enterococ- protein-protein interactions such as The XXXI edition of the European cus faecium, and S. aureus emphasizes protein modeling, genome functional School of Medicinal Chemistry (ES- the critical need to develop novel anti- annotation, protein structure analysis MEC) has been held as usual in the biotics to treat serious Gram-positive and characterization of protein-protein Renaissance scenario of Urbino from infections. In the second half of the ses- and protein-DNA complexes. The last July 3 to July 8, 2011. Of a total of 160 sion, Sergio Lociuro (THOT consulting two lectures given by Alessandro Pa- participants who have attended the this Sagl, Maroggia, CH) has focused on dova (Siena Biotech, I) and Kristian years edition, more than 65 % was con- new approaches to fight against bac- Strømgraard (University of Copenha- stituted by PhD, master of post-doctor- terial resistance like optimising “old” gen, DK) have focused the possibility ate students, 20 % by researchers from classes, searching new classes acting of modulating protein-protein interac- the academia and 15 % by researchers on “old” targets, searching new class- tions to find new therapies for cancer from industry. Although the participa- es acting on never exploited targets, and neurological disorders or chronic tion to the School is a requirement for neurodegenerative diseases. many Italian doctorate programs in me- The third session on Organo- and Bio- dicinal chemistry, and thus the majority Catalysis in the Synthesis of Bioactive of the registrants came from Italy, the Compounds has seen the presenta- about 20 % of non Italian participants tion of very interesting approaches and is an indication of the growing interest methodologies in organic synthesis that the School is gaining around Eu- directed to potential drug molecules. rope. Interest that this year was particu- preferring broad spectrum agents vs. Paolo Melchiorre (Institute of Chemi- larly pushed by the appealing scientific narrow spectrum vs. single pathogen cal Research of Catalonia, Tarragona, program, by the quality of the invited agents. Furthermore, Alan Kozikowski, E) in the opening lecture has addressed speakers, and by some fellowships of- with a second lecture on this topic, has the emerging field of aminocatalytic fered by the School, by EFMC, and by illustrated the use of high throughput cascade reactions that recently proved Farmindustria. In line with the well es- screening (HTS), medicinal chemistry, to be a new strategy to recreate the in- tablished format based on a four daily and cell biology in the discovery of new tricate structural scaffold and related sessions, this year the School has cov- drugs against resistant strains of TB. complex stereochemistry of natural-like ered the following topics: Infectious The second session was devoted to compounds with very high fidelity. The Diseases: Bacterial and Mycobacterial Protein-Protein Interactions (PPIs) in second talk, given by Marco Bella (Uni- Infections. The Problem of Bacterial Re- Drug Discovery and provided partici- versity “La Sapienza”, Roma, I) was sistance; Protein-Protein Interactions pants with an up-to-date overview of strictly connected to the previous one in Drug Discovery; Organo- and Bio- fundamental concepts and strategies, since it has given an overview of the Catalysis in the Synthesis of Bioactive as well as biophysical and computa- asymmetric organocatalysts which act Compounds; Hot Topics. tional approaches and tools in a field without the formation of any covalent The first session on Bacterial and My- of paramount importance. The first bond to the substrate. The third lecture, cobacterial Infections has seen Alan speaker, Kumlesh Dev (Trinity College by Marco Bandini (University of Bolo- Kozikowski (University of Illinois, USA) Dublin, IR), focused his talk on the new gna, I), has illustrated the advantages

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of the synthesis of complex molecules focused her talk on poly(ADP-ribose) discussed and the 10 best posters have provided by a combination of the orga- polymerases (PARPs) that are enzymes been selected for an oral presentation. no- with organometallo-catalysis. The activated by DNA strand breaks and A very interesting part of the School was last two lectures have been dedicated involved in DNA repair and on the ap- a round-table organized by Farmindus- to biocatalysis. Kurt Faber (University plication of PARP inhibitors in cancer tria, the Italian association of pharma of Graz (A) has presented the applica- therapy. In fact they are one of the first industries, to discuss on ‘Medicines tion of ene-reductase-mediated asym- classes of compounds that interact in and Public Private Partnerships: From metric synthesis to the preparation of a synthetic lethal manner with muta- Labs to Patients’. The meeting has seen several different bioactive compounds, tions in the genes encoding proteins a large and active participation of young whereas Roland Wohlgemuth (Sigma- involved in DNA repair. Some PARP researchers and PhD students. Aldrich, Buchs, CH) ha given an over- inhibitors, are now in clinical trials for As confirmed by the analysis of the view of biocatalytic transformations in BRCA1 or BRCA2 mutants tumors, for evaluation questionnaires completed the context of the growing importance triple-negative breast cancer, ovarian by participants, the School has certainly of metabolites as drugs, drug-derived cancer and other solid tumors. achieved its scientific and didactic aims, products, analytical standards, tools for The didactic program of the School thus confirming the success of a format elucidating biochemical pathways and was completed by two workshops on that nicely mixes up advanced semi- for metabolomic studies. protein-protein interactions in drug nars and didactic introductions and The last day has covered some hot top- discovery and on organo- and bio-catal- workshops. The informal environment ics. More in detail, recent progresses in ysis in the synthesis of bioactive com- and the appealing social program have the structure and function of ion chan- pounds, promoting a closer interaction also contributed to promote a produc- nels, transporters and G-protein cou- between students and lecturers and tive interchange between participants. pled receptors have been illustrated by among students with different back- In conclusion, the Scientific Committee Chris Ulens (Laboratory of Structural ground and know-how. Furthermore, hope that ESMEC-Urbino school could Neurobiology, Leuven, B) who showed the PhD students following the last year contribute to keep at a very high level how the several three-dimensional of PhD course and them coming from the didactic offer of the EFMC. With structures of GPCR, ion channels and foreign countries have been invited to the hope to continue along this way, the transporter now available may help present a poster on their research dur- organizers are looking forward to see- the design of specific modulators. Ol- ing two poster sessions, where results ing you in Urbino for the XXXII edition, ivier Bezencons (Actelion Pharmaceuti- and methodologies have been freely in July 2012. cals Ltd, Allschwil, CH), starting from Aliskiren, the first Direct Renin Inhibi- tor (DRI) clinically available, presented the discovery of a new class of DRI with a piperidine-based structure; one of these compounds, ACT-077825 is pres- ently in clinical trials for the treatment of hypertension. Henk Stunnenberg (Radboud University, Nijmegen, NL) showed how the systems biology ap- proach, which considers the cell as a system whose components interact in a certain way in normal conditions or in response to a chemical or genetic per- turbation, can be applied to find treat- ments for leukemia. The last speaker of this edition was Nicola Curtin (Univer- sity of Newcastle upon Tyne, UK). She

MCW 84 News from the Societies by erden banoglu

THE BIOLOGICAL AND MEDICINAL The Biological and Medicinal Chemis- target for antimalarial drugs’ while the CHEMISTRY SECTOR OF THE RSC try Sector (BMCS) Postgraduate Sym- poster prize went to Rebecca Nonoo, posium on Biological and Medicinal also from Imperial College, for her work Malcolm Campbell Memorial Prize 2011 Chemistry was held in the Department titled ‘Towards kinetic template-guided The Biological and Medicinal Chemistry of Chemistry at the University of Cam- tethering of fragments’ Sector of the RSC is proud to announce bridge on Friday 10th December 2010. Advance notice: the 2011 symposium will the winner of the Malcolm Campbell Me- This annual symposium for PhD and be held in the Department of Chemis- morial Prize for 2011. The prize has been postdoctoral students working in bio- try at the University of Cambridge from awarded to the Liverpool team of Paul logical chemistry, medicinal chemistry, 1000 to 1800 on Friday 9th December M. O’Neill, B. Kevin Park and Stephen A. or related areas event aims to provide 2011. Ward for work in the area of antimalarial students working in these fields with an drug discovery and chemical biology of opportunity to present their research Plasmodium falciparum. work in public and also to learn a little The Malcolm Campbell Memorial prize about the drug discovery and develop- commemorates Professor Campbell’s ment process. The programme included outstanding contributions in a broad keynote lectures by Professor Barry Pot- range of chemistry and their applications ter from the School of Pharmacy at the to the understanding of bioactivity. The University of Bath, one of the winners of prize is awarded biennially and the 2011 the 2009 Malcolm Campbell Award, Dr prize will be formally presented to the Steve Lindell from Bayer CropScience in winning team during the RSC/SCI Me- Germany and Dr Matt Tozer from Peak- Zhiyong Yu from the Department of Chemistry, Im- perial College, winner of the oral presentation prize dicinal Chemistry Symposium to be held dale Molecular. There is no registration at the symposium, being presented with his cheque in Cambridge, 11th-14th September 2011. fee for the symposium which was at- for £250 by Professor Barry Potter from the School of The BMCS Committee wishes to express tended by 140 students from across the Pharmacy, University of Bath. its gratitude for the high quality entries UK as well as one participant from Italy from both academia and industry for the and one from the USA. 2011 award. Details of the Award may be There were also nine oral presentations found here [http://www.rsc.org/Member- and 20 poster presentations from stu- ship/Networking/InterestGroups/BMCS/ dents, whose work covers cutting edge Activities/CampbellAward.asp] and details research in the areas of biological chem- of forthcoming RSC-BMCS events may be istry and drug discovery, potentially found here: http://www.rsc.org/Member- leading to advances which could posi- ship/Networking/InterestGroups/BMCS/ tively influence the future of drug treat- ForthcomingEvents.asp. ment. Prizes were awarded for the best presentations with the oral prize going BMCS Postgraduate Symposium for to Zhiyong Yu from Imperial College for Rebecca Nonoo from the Department of Chemistry, Biological and Medicinal Chemistry his work titled ‘Design and synthesis of Imperial College, winner of the poster presentation 10th December, 2010 at the Chemistry Inhibitors for Plasmodium falciparum prize at the symposium, being presented with her cheque for £100 by Professor Barry Potter from the Department, Cambridge University N-MyristoylTransferase: a promising School of Pharmacy, University of Bath.

MCW 85 MEDCHEMWATCH NO.13 AUGUST 2011

THE MEDICINAL CHEMISTRY This year’s symposium with six invited DIVISION OF MEDICINAL DIVISIONS OF THE TWO lectures and three oral communications CHEMISTRY OF THE SWISS BELGIAN CHEMICAL SOCIETIES, is scheduled to be held on Friday No- CHEMICAL SOCIETY “KONINKLIJKE VLAAMSE vember 25, 2011, at the conference centre News on planned activities 2011 and 2012 CHEMISCHE VERENIGING (KVCV)” “Het Pand” in Ghent and will be chaired AND “SOCIÉTÉ ROYALE DE CHIMIE by Prof. Serge Van Calenbergh (UGent). Division of Medicinal Chemistry, oral and (SRC)” The title and focus of the symposium will poster session at the Fall Meeting of the be “Emerging Targets and Treatments: Swiss Chemical Society Opportunities and Challenges for Drug EPFL, Lausanne, September 9, 2011 Emerging Targets and Treatments: Op- Design”. portunities and Challenges for Drug De- Division of Medicinal Chemistry, oral and sign. Annual One-Day Meeting on Me- poster session at the Fall Meeting of the dicinal Chemistry of SRC & KVCV Confirmed Speakers to date: Swiss Chemical Society Het Pand, Ghent ETH Zürich, Zürich, September 13, 2012 November 25, 2011 Translocator protein as a promising Website: www.medchem.be target for novel anxiolytics A half-day mini-symposium at the Univer- Contact: LD Organisation Scientific Prof. Federico DA SETTIMO sity of Basel in May 2012. (the exact date Conference Producers Università di Pisa, Pisa, Italy and topic of the event will be announced). Mail: [email protected] Drug to Genome to Drug: Discovery of The Medicinal Chemistry Divisions of New Antiplasmodial Compounds MEDCHEM GROUP OF THE the two Belgian Chemical Societies, Prof. Benoit DEPREZ PORTUGUESE CHEMICAL SOCIETY “Koninklijke Vlaamse Chemische Ve- Université de Lille 2, Lille, France News on planned activities 2011 and 2012 reniging (KVCV)” and “Société Royale de Chimie (SRC)” are organizing every Selective Androgen Modulators (SARM) “1st Fall School on Medicinal Chemistry”, year an international one day symposi- for the Treatment of Cachexia Fátima, Portugal um in Belgium, with the aim to update Mr. Pierre DEPREZ November 20-23, 2011 interested participants on selected ar- Galapagos, Romainville, France The Medicinal Chemistry Group of the eas of pharmaceutical research by spe- Portuguese Chemical Society will run the cialists in their respective field. Therapeutic Targeting of Toll-like first Fall School on Medicinal Chemistry In recent years, this symposium has Receptors ever held in Portugal, to celebrate the UN been focusing on topics such as “Does Dr. Brian KEOGH International Year of Chemistry 2011. It size matter? Beyond small molecule Opsona Therapeutics Ltd, Dublin, Ireland will cover a range of key topics in drug dis- therapeutics: challenges and success covery and translational research related stories“ (2009), “Small molecules, An- Targeting GSK-3 with ATP Non- to cancer and neurodegenerative diseas- tibodies and Natural Products: Multiple Competitive Inhibitors: From the Bench es and targets scientists from academia Faces of Medicinal Chemistry” (2008); to the Clinical Trials and pharmaceutical industry, as well as “New Drugs and Drug Candidates: Re- Prof. Ana MARTINEZ Ph.D. students. cent Achievements in Medicinal Chem- Instituto de Quimica Medica-Csic, istry (2007)”; “Personalized Medicine: Madrid, Spain Third National Meeting on Medicinal New Opportunities for Drug Discovery Chemistry (ENQT3) (2006)”, or “Targeting the Brain: Suc- New targets for the treatment of HIV Aveiro University, Portugal. cesses and Pitfalls (2005)”, and has Dr. David PRYDE November, 2012 been gathering every year around 170 to Pfizer Global R&D, Sandwich, The third edition of the now traditional 200 participants, half from universities, United Kingdom National Meeting on Medicinal Chem- half from industry, both from Belgium istry will take place in the University of and surrounding countries. Aveiro.

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EFMC ISMC 2012 XXIInd International Symposium on Medicinal Chemistry

September 2-6, 2012 Berlin, Germany

Mark the dates!

INTERNATIONAL ORGANISING COMMITTEE SYMPOSIUM SECRETARIAT

Chairmen LD Organisation Sprl Bernd CLEMENT Scientific Conference Producers (Pharmazeutisches Institut der Universität Kiel, Germany) Rue Michel de Ghelderode 33/2 Eckhard OTTOW 1348 Louvain-la-Neuve, Belgium (Bayer Schering Pharma AG, Germany) tel: +32 10 45 47 77 fax: +32 10 45 97 19 Members mail: [email protected] Koen AUGUSTYNS (University of Antwerp, Belgium) Rasmus P. CLAUSEN (University of Copenhagen & EFMC, Denmark) PLENARY LECTURES Edmond DIFFERDING (Differding Consulting, Belgium) Rui MOREIRA 4 INVITED PLENARY LECTURES (University of Lisbon, Portugal) 3 EFMC AWARD LECTURES Henk TIMMERMAN – The Nauta Award for Pharmacochemistry (VU University Amsterdam, The Netherlands) – The UCB-Erlich Award for Excellence in Medicinal Chemistry – The Prous Institute-Overton and Meyer Award for New Technologies in Drug Discovery 2 EFMC PRIZE LECTURES – Prize for Young Medicinal Chemist in Industry – Prize for Young Medicinal Chemist in Academia

www.ismc2012.org