Medchemwatch

The o;cial EFMC e-newsletter MedChemWatch 7July 2009 Editorial IN THIS ISSUE 1 I EDITORIAL Dear Colleagues, 1 I Council approves the launch of the launch of a new journal is always welcome as a sign of vitality for a scientific MedChemComm community, but the announcement by Gerhard Ecker, in the article below, of MedChemComm, a new journal of the Royal Society of Chemistry (RSC) for rapid 3 I PERSPECTIVE communications in medicinal chemistry, has a special impact for EFMC (and, in Virtual Screening: what are we missing? some respect, also for our newsletter…). MedChemComm, whose first issue is expected to be released by mid 2010, is the 5 I LAB PRESENTATION result of a partnership between RSC and EFMC, both strongly committed in en- The Department of Biomolecular suring the new journal with a very high scientific level and an excellent technical Systems – Max-Planck Institute for quality. Colloids and Surfaces, Potsdam continued on p.2 » 7 I SME PRESENTATION – Chemotargets Council approves the launch of MedChemComm – Inte:Ligand At the meeting in Budapest the Council approved the proposal of the Royal Society 9 I YOUNG RESEARCHER for Chemistry to jointly launch MedChemComm, which will be the official journal Karl Gademann of EFMC. In analogy to Chemical Communications, MedChemComm will focus on prelimi- 10 I NEWS FROM THE SOCIETIES nary articles in communications format. Presenting new ideas and concepts in the area of Medicinal Chemistry, MedChemComm will include new studies related 12 I EFMC EVENTS to biologically-active chemical or biochemical entities that can act as pharmacolo- gical agents with therapeutic potential or relevance. The journal will be suitable 15 I EFMC COMMITTEES for readers from both academia and industry, conducting research in the field of Industrial Liaison Committee medicinal chemistry, drug discovery, pharmacology and pharmaceutical research. This will include traditional areas of the chemical sciences together with topics at 16 I EFMC NEWS the interface with biology and physics. The journal will act globally with regional offices in Europe, Asia and Northern America. The first issue is expected by mid of next year. Gerhard Ecker President, EFMC 1 Editorial MedChemWatch no.7 July 2009 « continued from p. 1 EFMC does not publish the journal by itself, but cooperates with RSC, a non profit organization, to sponsor and influence a cutting-edge journal in the field of medicinal chemistry with the very ambitious scope of assuring a top-quality instrument to disseminate rapid communications. MedChemComm will not overlap with established journals, but rather will complement, in worldwide oriented way, the existing offer of high quality publications with specific focus and scope. In some ways, the launch of MedChemComm is the ‘end of the beginning’ of a long story between EFMC and scientific journals. The special nature of EFMC as a federation of Societies, prevents the creation of its own journal, not only for reasons related to national languages but also for the commitment of many national societies in publishing their own, often very well reputed, journals. Don’t miss, in this respect, a very interesting article by Henk Timmerman which will be published in the next issue of the newsletter. The partnership between RSC and EFMC is an attempt, I am sure very successful, to conciliate the demand for a presence of EFMC to drive journal strategies with the need of preserving the identity and the scope of existing of national and private initiatives. As a part of the agreement, the paper issues of MedChemComm will also contain our newsletter. We will continue to distribute the newsletter to all the registered members through the e.mail list, and the newsletter will be available through the EFMC web site (www.efmc.info/medchemwatch). MedChemComm will be another, important, way to disseminate information. We are sure that having the newsletter coming together with a scientific journal will increase the visibility of the contents and will also increase the eagerness of authorship. Thus, I strongly advise everyone would like to contribute to send us small articles, or comments, or suggestions, and it will be our commitment to give them the highest visibility. This issue of MedChemWatch, the number seven in the series, contains very interesting presentations and some innovations. Gisbert Schneider comments, in his Perspective, the state of the art of Virtual Screening in drug discovery, and I am sure his thoughtful contribution will stimu- late debate. Peter Seeberger, winner of the 2008 UCB Award for Excellence in Medicinal Chemistry, presents his new lab, at the Department of Biomolecular Systems – Max-Planck Institute for Colloids and Surfaces, Potsdam. The idea of presenting laboratories of excellence around Europe aims at dissemi- nating the top quality level of research, but also at providing information for potential collaborations, graduate and post-graduate positions, or for the identification of common research interest. On this basis, we thought it as appropriate to extend these presentations also to labs driven by younger researchers and to SMEs. Two SMEs, Chemotargets and Inte:ligands, and one lab, driven by Karl Gademann at the Ecole Polytechnique Federale de Lausanne (EPFL), open this series. Ideas and suggestion for future contributions are very welcome ! Last, but not the least, have a look to the EFMC events. Also for the remaining part of this year 2009 and for 2010, there is a plenty of symposia, accredited and sponsored schools, and short courses which surely fit with the interests and needs of European medicinal chemists. Gabriele Costantino Editor 2 Perspective Virtual Screening: what are we missing? by gisbert schneider Virtual screening 80-85% accuracy at best in retrospec- any such “global” method (admittedly, for druglike mol- tive tests, and 40-50% as an optimistic the differentiation between local and ecules in general estimate in prospective applications. It global models is artificial itself and will – and new agents is therefore only fair to ask for the rea- not resolve the underlying discrepancy with a defined phar- sons for this notorious threshold, as it between the expected model quality macological profile is almost impossible to judge the real and a poor representation of molecu- in particular – is an value of “just another virtual screen- lar objects). established concept ing method” being published with a Furthermore, probably all macromo- for hit and subsequent lead candidate reported accuracy of 85.3% leading lecular drug targets tolerate various identification during the early phases to some low affinity hits at a selected structurally diverse ligand chemotypes, of a drug discovery project, sometimes target. Simply demanding for “better which as yet has not been sufficiently even in situations with much structur- training data” is insufficient, often un- taken into consideration during model al uncertainty and potential ambiguity justified, and cannot be presented as development. Future virtual screening of receptor-ligand interactions (Figure the only solution – despite the well- methods must be able to account for 1). known deficiencies of primary HTS one-to-many and many-to-many rela- Coined as a term approximately a data and error-prone readouts of some tionships between ligands and targets, decade ago, virtual screening today cell-based assays, to name but a few. which will render them useful for off- stands for a rather loosely defined col- So, what are we missing? Which infor- target prediction, as well as target and lection of computational methods for mation will be essential for progress ligand “de-orphanization”. Appropri- screening compound prioritization in method development? It is the au- ate data from chemo- and pharmacog- and design. Although many elegant thor’s opinion that an answer to this enomics initiatives should play a key and successful applications of these question will have to address at least role here and serve as reference. techniques have been published over the following critical points: Finally, as long as entropic contribu- the past years, for example those based Foremost, we cannot expect practical tions to receptor-ligand interactions on automated ligand-receptor dock- applications of any virtual screening are grossly neglected, sustained suc- ing or machine learning classifiers, it method to produce perfect results sim- cess by virtual screening will be pos- is most noteworthy that there are al- ply because no model is perfect (and sible only for a limited set of drug- most as many methods as are report- sometimes expectations are borderline receptor complexes. While progress is ed practical applications. There is no silly: “If virtual screening does not pro- being made for the modeling of water single best virtual screening technique duce novel hits with nanomolar affin- molecules involved in ligand binding, which has emerged as the tool for hit ity it is useless.”). flexible fit phenomena, ligand protona- identification irrespective of the drug To strive for perfect prediction of bio- tion states in proteinous environments, target under consideration. While it is chemical response profiles for a given and quantitative interaction types, reli- evident that the applicability and thus screening compound is unrealistic and able entropy estimations remain com- the usefulness of a certain method are bears the risk of leading to artifactual, putationally impracticable for high- target-dependent properties, a peculiar over-trained models. While a perfect throughput virtual screening. New observation is that current prediction “local” prediction model for a certain concepts are urgently needed to ad- software solutions (e.g., for “drug-like- lead series and a defined target certain- dress this critical issue. This will have ness”, pharmacokinetic parameters, ly is worthwhile building, it simply is to include a fresh view on the existing target-ligand binding) rarely exceed unreasonable to expect perfection from physically and partly mechanistically 3 Perspective MedChemWatch no.7 July 2009 motivated molecular force fields.

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