Part I Introduction to Lead Generation
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FDA-Approved Drugs with Potent in Vitro Antiviral Activity Against Severe Acute Respiratory Syndrome Coronavirus 2
pharmaceuticals Article FDA-Approved Drugs with Potent In Vitro Antiviral Activity against Severe Acute Respiratory Syndrome Coronavirus 2 1, , 1, 2 1 Ahmed Mostafa * y , Ahmed Kandeil y , Yaseen A. M. M. Elshaier , Omnia Kutkat , Yassmin Moatasim 1, Adel A. Rashad 3 , Mahmoud Shehata 1 , Mokhtar R. Gomaa 1, Noura Mahrous 1, Sara H. Mahmoud 1, Mohamed GabAllah 1, Hisham Abbas 4 , Ahmed El Taweel 1, Ahmed E. Kayed 1, Mina Nabil Kamel 1, Mohamed El Sayes 1, Dina B. Mahmoud 5 , Rabeh El-Shesheny 1 , Ghazi Kayali 6,7,* and Mohamed A. Ali 1,* 1 Center of Scientific Excellence for Influenza Viruses, National Research Centre, Giza 12622, Egypt; [email protected] (A.K.); [email protected] (O.K.); [email protected] (Y.M.); [email protected] (M.S.); [email protected] (M.R.G.); [email protected] (N.M.); [email protected] (S.H.M.); [email protected] (M.G.); [email protected] (A.E.T.); [email protected] (A.E.K.); [email protected] (M.N.K.); [email protected] (M.E.S.); [email protected] (R.E.-S.) 2 Organic & Medicinal Chemistry Department, Faculty of Pharmacy, University of Sadat City, Menoufia 32897, Egypt; [email protected] 3 Department of Biochemistry & Molecular Biology, Drexel University College of Medicine, Philadelphia, PA 19102, USA; [email protected] 4 Department of Microbiology and Immunology, Zagazig University, Zagazig 44519, Egypt; [email protected] 5 Pharmaceutics Department, National Organization for Drug Control and Research, Giza 12654, Egypt; [email protected] 6 Department of Epidemiology, Human Genetics, and Environmental Sciences, University of Texas, Houston, TX 77030, USA 7 Human Link, Baabda 1109, Lebanon * Correspondence: [email protected] (A.M.); [email protected] (G.K.); [email protected] (M.A.A.) Contributed equally to this work. -
Second Generation Inhibitors of BCR- ABL for the Treatment of Imatinib- Resistant Chronic Myeloid Leukaemia
REVIEWS Second generation inhibitors of BCR- ABL for the treatment of imatinib- resistant chronic myeloid leukaemia Ellen Weisberg*, Paul W. Manley‡, Sandra W. Cowan-Jacob§, Andreas Hochhaus|| and James D. Griffin¶ Abstract | Imatinib, a small-molecule ABL kinase inhibitor, is a highly effective therapy for early-phase chronic myeloid leukaemia (CML), which has constitutively active ABL kinase activity owing to the expression of the BCR-ABL fusion protein. However, there is a high relapse rate among advanced- and blast-crisis-phase patients owing to the development of mutations in the ABL kinase domain that cause drug resistance. Several second-generation ABL kinase inhibitors have been or are being developed for the treatment of imatinib- resistant CML. Here, we describe the mechanism of action of imatinib in CML, the structural basis of imatinib resistance, and the potential of second-generation BCR-ABL inhibitors to circumvent resistance. The BCR-ABL oncogene, which is the product of the design of new drugs to circumvent resistance, and Philadelphia chromosome (Ph) 22q, encodes a chimeric several new agents have been developed specifically BCR-ABL protein that has constitutively activated ABL for this purpose. These compounds have been well tyrosine kinase activity; it is the underlying cause of characterized for efficacy against the mutant enzymes chronic myeloid leukaemia (CML)1–3. Whereas the 210 in preclinical studies, and impressive therapeutic activ- kDa BCR-ABL protein is expressed in patients with ity has now been reported for two second generation CML, a 190 kDa BCR-ABL protein, resulting from an drugs in phase I and II clinical trials in patients with *Dana Farber Cancer alternative breakpoint in the BCR gene, is expressed in imatinib-resistant CML. -
Medicinal Chemistry
Medicinal Chemistry Dr. Shuaib Alahmad Medicinal and Pharmaceutical Chemistry References: 1- Wilson and Gisvold’s Text book of Organic Medicinal & Pharmaceutical Chemistry, Twelfthe Edition, 2011 2- Gareth Thomas’’ Medicinal Chemistry; An Introduction,2nd Edition. 2007. 3- Dr.Iyad Allous lectures 2 Introduction Medicinal Chemistry: is the discovery, the development, the identification and the interpretation of the mode of action of biologically active compounds that can be used as drugs for the prevention, treatment or cure of human and animal diseases. Medicinal chemistry includes the study of already existing drugs, of their biological properties and their structure-activity relationships. During the early stages of medicinal chemistry development, scientists were primarily concerned with the isolation of medicinal agents found in plants. Today, scientists in this field are also equally concerned with the creation of new synthetic compounds as drugs. Medicinal chemistry is devoted to the discovery and development of new agents for treating diseases. 3 Introduction The primary objective of Medicinal Chemistry is the design and discovery of new compounds that are suitable for use as drugs. This process involves a team of workers from a wide range of disciplines such as chemistry, biology, biochemistry, pharmacology, mathematics, medicine and computing, amongst others 4 Introduction Medicinal chemistry covers the following stages: I.The first stage is lead discovery in which new active substances or drugs are identified and prepared -
Molecular Obesity, Potency and Other Addictions in Drug Discovery
Molecular Obesity, Potency and other Addictions in Drug Discovery Mike Hann Bio-Molecular Structure MDR Chemical Sciences GSK Medicines Research Centre Stevenage, UK [email protected] The challenge of drug discovery – Patients are still in need of more effective drugs for many diseases. – Payers are increasingly only prepared to pay for innovative rather than derivative drugs. – Investors believe they can get a better return on investment elsewhere – Legislators are demanding that only the very safest possible drugs are licensed. – Researchers are equally frustrated – despite all the accumulated knowledge from the new technologies, the challenge of successfully navigating through everything to find novel drugs seems to get harder rather than easier. – the fruit is possibly not as low hanging as before – The consequence of all this is that the average cost is now $1.8bn*! – We owe it to patients and society to do better than this. – *How to improve R&D productivity: the pharmaceutical industry's grand challenge. S. M. Paul, D. S. Mytelka, C. T. Dunwiddie, C. C. Persinger, B. H. Munos, S. R. Lindborg and A. L. Schacht, Nat. Rev. Drug Discovery, 2010, 9, 203. Learning from our mistakes – the resurgence of reason based on metadata from big Pharma Emergence of rules of thumb as guidance – Permeability/solubility: Pfizer analysis of existing drugs and oral absorption profile – (Lipinski, Adv. Drug. Del. Revs. 1997, 23, 3) – Mol Wt <500, LogP <5, OH + NH count <5, O + N count <10: 90% of oral drugs do not fail more than one of these rules. – Lipinski Rule of 5 – Receptor Promiscuity: AZ analysis of 2133 compounds in >200 Cerep Bioprint® assays – (Leeson & Springthorpe, Nat. -
Improving Drug Discovery Efficiency Via in Silico Calculation of Properties
Improving Drug Discovery Efficiency via In Silico Calculation of Properties D. Ortwine 1 16th North American Regional ISSX meeting , 10/18/09 Outline • Background: Why Calculate Properties? • Calculable properties • Modeling Methods and Molecule Descriptors • Reporting Results From Calculations • Available Commercial Software • Strategies for Implementation • A Real Project Example • The Future • Conclusions • References 2 16th North American Regional ISSX meeting , 10/18/09 Lead Optimization in Drug Discovery The Needle in the Haystack 3 16th North American Regional ISSX meeting , 10/18/09 Why Calculate Properties? They can be related to the developability of drugs! Most marketed oral drugs have defined “property profiles” Paul D. Leeson and Brian Springthorpe, “The Influence of Drug-Like Concepts on Decision-Making in Medicinal Chemistry”, Nature Reviews Drug Discovery, vol. 6, pp. 881-890, 2007. Mark C. Wenlock, et.al, “A Comparison of Physiochemical Property Profiles of Development and Marketed Oral Drugs”, J. Med. Chem, 2003, 46, 1250-1256. 4 16th North American Regional ISSX meeting , 10/18/09 Why Calculate Properties? They can also be related to the ADMET Profile M. Paul Gleeson. Generation of a Set of Simple, Interpretable ADMET Rules of Thumb. J. Med. Chem. (2008), 51(4), 817-834. 5 16th North American Regional ISSX meeting , 10/18/09 Why Calculate Properties? • Prioritize synthesis -> Generate virtual individual molecules or combinatorial libraries, calculate properties, map back to R groups • Build an understanding of SAR • -
Topic 7 Drug Discovery and Design Pt. 1
Topic 7 Drug Discovery and design Pt. 1 Chapter 9 Patrick Contents Part 1: Sections 9.1-9.3 1. Target disease 2. Drug Targets 3. Testing Drugs 3.1. In vivo Tests 3.2. In vitro Tests 3.2.1. Enzyme Inhibition Tests 3.2.2. Testing with Receptors DRUG DESIGN AND DEVELOPMENT Stages 1) Identify target disease 2) Identify drug target 3) Establish testing procedures 4) Find a lead compound 5) Structure Activity Relationships (SAR) 6) Identify a pharmacophore 7) Drug design- optimising target interactions 8) Drug design - optimising pharmacokinetic properties 9) Toxicological and safety tests 10) Chemical development and production 11) Patenting and regulatory affairs 12) Clinical trials 1. TARGET DISEASE Priority for the Pharmaceutical Industry • Can the profits from marketing a new drug outweigh the cost of developing and testing that drug? Questions to be addressed • Is the disease widespread? (e.g. cardiovascular disease, ulcers, malaria) • Does the disease affect the first world? (e.g. cardiovascular disease, ulcers) • Are there drugs already on the market? • If so, what are there advantages and disadvantages? (e.g. side effects) • Can one identify a market advantage for a new therapy? 2. DRUG TARGETS-Remember? A) LIPIDS Cell Membrane Lipids B) PROTEINS Receptors Enzymes Carrier Proteins Structural Proteins (tubulin) C) NUCLEIC ACIDS DNA RNA D) CARBOHYDRATES Cell surface carbohydrates Antigens and recognition molecules 2. DRUG TARGETS TARGET SELECTIVITY Between species • Antibacterial and antiviral agents • Identify targets which are unique to the invading pathogen • Identify targets which are shared but which are significantly different in structure Within the body • Selectivity between different enzymes, receptors etc. -
Chapter 7. Fragment-Based Drug Discovery
CHAPTER 7 Fragment-Based Drug Discovery Venkata Velvadapu1, Bennett T. Farmer2 and Allen B. Reitz1 1Fox Chase Chemical Diversity Center, Inc., Doylestown, PA, USA; 2Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA OUTLINE I. LigandÀProtein Interactions: First C. SAR by Mass Spectroscopy 171 Principles 162 D. Interferometry and Isothermal Titration A. Binding Energy as the Sum of the Parts 162 Calorimetry 171 B. Historical Development 162 E. Virtual Screening 172 C. First Principles: Ligand Efficiency 163 VI. Fragment Merging/Linking/Growing 172 II. What is Fragment-Based Drug Discovery? 164 A. Fragment Merging 172 A. Overview of FBDD 164 B. Fragment Linking 172 B. The Concept of FBDD 165 C. Fragment Growing 173 C. Fragments in FBDD 165 VII. Fragment Hit Follow-Up, and Pitfalls D. Fragments Hits vs. HTS Hits 165 to Avoid 174 III. Creation and Analysis of FBDD Libraries 166 A. How to Best Reduce False Positives A. Fragment Library Design 166 (NMR, MS) and False Negatives (X-ray) 174 B. Analysis of Fragments 167 B. Isothermal and Isothermal Titration C. The Role of the Medicinal Chemist in Calorimetry and Further Secondary FBDD 167 Analysis 174 C. Pitfalls to Avoid 175 IV. Fragment Screening Methods 167 A. Nuclear Magnetic Resonance 168 VIII. Zelborafs, First Approved Drug from B. 2D (protein-based) Screening 169 FBDD 175 C. X-ray Crystallography 169 IX. Limitations of FBDD 176 V. Other Biochemical and Biophysical X. Trends for the Future 176 Methods 171 A. Substrate Activity Screening 171 References 177 B. SPR Spectroscopy 171 Learn from yesterday; live for today; hope for tomorrow. -
Hit Discovery and Hit-To-Lead Approaches Reviews
Drug Discovery Today Volume 11, Numbers 15/16 August 2006 REVIEWS POST SCREEN Hit discovery and hit-to-lead approaches Reviews Gyo¨ rgy M. Keseru˝ 1 and Gergely M. Makara2 1 CADD&HTS Unit, Gedeon Richter Ltd, 19-21 Gyo¨mro˝iu´t, Budapest, H-1103, Hungary 2 Merck Research Laboratories, Merck & Co, RY80Y-325, 126 E. Lincoln Ave, Rahway, New Jersey, 07065, USA Hit discovery technologies range from traditional high-throughput screening to affinity selection of large libraries, fragment-based techniques and computer-aided de novo design, many of which have been extensively reviewed. Development of quality leads using hit confirmation and hit-to-lead approaches present their own challenges, depending on the hit discovery method used to identify the initial hits. In this paper, we summarize common industry practices adopted to tackle hit-to-lead challenges and review how the advantages and drawbacks of different hit discovery techniques could affect the various issues hit-to-lead groups face. It has been shown that marketed drugs are very frequently highly All hit discovery approaches have – often orthogonal – short- similar to the leads from which they were derived [1]. Thus, both comings prompting the frequent use of multiple techniques for hit the quality and the quantity of lead classes available to medicinal confirmation (Table 1). Challenges facing traditional HTS tech- chemists are primary drivers for discovering best-in-class medi- nologies include high false-positive rates, the need for reporter cines. This makes lead generation a crucial step in the drug dis- assays and the limitation in throughput imposed by testing com- covery process. -
Drug Development
DRUG DEVELOPMENT www.acuteleuk.org Drug Development Process Only about 2% of substances evaluated in early research make it to the market as new medicines Number of drugs in the R&D pipeline Number of drugs in the R&D pipeline worldwide 2019 vs. 2020, by development phase Source: https://www.statista.com/ A minimum of a 10-year plan It takes over 10 years and on average costs between €400 million and €1.5 billion before a new medicine can be made available to patients and reimbursement starts Drug development means … What is the rationale to initiate drug development ? • Scientific and Intellectual Property – How does the drug work? • Molecule structure and properties • Mechanism of action • Biological activity (bioassays, drug/target interaction, affinity, specificity,…) – What data support the approach? • Literature validation • In-house preclinical/clinical data – Who owns the intellectual property? What is the rationale to initiate drug development ? • Disease overview and unmet medical need – What is known about disease pathogenesis (translational medicine)? – Where in the disease process should drug enter? Greatest unmet need? – Is this disease part of a disease family? If so which fits best with drug and regulatory history? Is there an orphan approach? – Is this disease field crowded? – Has the indication been clinically studied before (in drug studies)? – What is the event rate for target medical problems? (Make the statisticians happy) – Are there “approvable” endpoints for the unmet needs? – If not, what endpoints seem reasonable: -
Fragment-Based Drug Discovery
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 1999 Fragment-based drug discovery Novel methods and strategies for identifying and evolving fragment leads EDWARD A. FITZGERALD ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6214 ISBN 978-91-513-1106-7 UPPSALA urn:nbn:se:uu:diva-429950 2021 Dissertation presented at Uppsala University to be publicly examined in A1:107a, BMC (Biomedicinsk Centrum), Husargatan 3, Uppsala, Wednesday, 24 February 2021 at 09:15 for the degree of Doctor of Philosophy. The examination will be conducted in English. Faculty examiner: Professor Hanna-Kirsti Schrøder Leiros (UiT The Arctic University of Norway). Abstract FitzGerald, E. A. 2021. Fragment-based drug discovery. Novel methods and strategies for identifying and evolving fragment leads. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 1999. 59 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-513-1106-7. The need for new drugs became ever more apparent in the year 2020 when the world was faced with a viral pandemic. How drugs are discovered and their relevance to society became part of daily discussions in workplaces and homes throughout the world. Consequently, efficient strategies for preclinical drug discovery are clearly needed. The aim of this thesis has been to contribute to the drug discovery process by developing novel methods for fragment-based drug discovery (FBDD), a rapidly developing approach where success relies on access to sensitive and informative analytical methods as well as chemical compounds with suitable properties. This process is fundamentally dependent on the interplay between scientists and engineers across biology, chemistry and physics. -
Multi-Parameter Optimisation in Drug Discovery
Discovery Technology Multi-Parameter Optimisation in Drug Discovery Drug discovery activities are producing ever-larger volumes of By Matthew Segall at Optibrium Ltd complex data that carry significant levels of uncertainty; multi- parameter optimisation methods enable this data to be better utilised to quickly target compounds with a good balance of properties – but they all have their strengths and weaknesses. One of the major challenges of drug discovery is to a compromise on less important properties in order to identify a compound with a good balance of the achieve critical requirements. many physicochemical and biological properties necessary to become a successful, efficacious and safe The challenge of simultaneously optimising multiple drug. Having identified poor pharmacokinetics (PK) factors has been previously addressed in many fields, as a major cause of clinical failure in the later 1990s, from engineering disciplines such as automotive projects now routinely attempt to mitigate this risk and aeronautical design, to economics. The methods by assessing the absorption, distribution, metabolism used to achieve this are described as multi-parameter and elimination (ADME) properties of compounds in optimisation (MPO), multi-dimensional optimisation early drug discovery. However, more recently, safety has (MDO) or multi-objective optimisation (MOOP). For become a greater cause of failure in the clinic leading to simplicity, we will use the term MPO to refer to all of the assessment of toxicity earlier in the drug discovery these methods. We can learn from these approaches process. The result has been an increase in cost and to better use the data generated in drug discovery a reduction in the productivity of drug discovery, but in order to quickly design and select compounds unfortunately a corresponding increase in the success with a good balance of properties. -
Part I the Concept of Fragment-Based Drug Discovery
1 Part I The Concept of Fragment-based Drug Discovery 3 1 The Role of Fragment-based Discovery in Lead Finding Roderick E. Hubbard 1.1 Introduction Fragment-based lead discovery (FBLD) is now firmly established as a mature col- lection of methods and approaches for the discovery of small molecules that bind to protein or nucleic acid targets. The approach is being successfully applied in the search for new drugs, with many compounds now in clinical trials (see summary in [1]) and with the first fragment-derived compound now treat- ing patients [2]. The approach has also had a number of other impacts such as providing starting points for lead discovery for challenging, unconventional targets such as protein–protein interactions [3–5], increasing the use of bio- physics to characterize compound binding and properties, and providing small groups, particularly in academia, with access to the tools to identify chemical probes of biological systems [6,7]. The other chapters in this book will discuss the details and new advances in the methods and provide examples of how fragments have been used in specific projects. In this chapter, I will draw on my own experiences and view of the literature to discuss three main areas. First, I will review current practice in FBLD, highlighting how and when fragments have an impact on the drug discov- ery process. Second, I will then review how the ideas have developed, with par- ticular emphasis on the past 10 years. I will discuss how fragment methods and thinking have been extended and refined and how these developments have affected the lead discovery process in drug discovery.