Drug Design Strategies: Quantitative Approaches
This book brings together drug design practitioners, all leaders in their field, who are actively advancing the field of quantitative methods to guide drug discovery, from structure-based design to empirical statistical models - from rule-based approaches to toxicology to the fields of bioinformatics and systems biology. The aim of the book is to show how various facets of the drug discovery process can be addressed in a quantitative fashion (ie: numerical analysis to enable robust predictions to be made). Each chapter includes a brief review of the topic showing the historical development of quantitative approaches, a survey/summary of the current state-of-the-art, a selection of well chosen examples with some worked through and an appreciation of what problems remain to be overcome as well as an indication of how the field may develop. After an overview of quantitative approaches to drug design the book describes the development of concepts of "drug-like properties", of quantitative structure-activity relationships and molecular modelling, and in particular, structure-based design approaches to guide lead optimisation. How to manage and describe chemical structures, underpins all quantitative approaches to drug design and these are described in the following chapters. The next chapter covers the value of a quantitative approach, and also the challenge which is to describe the confidence in any prediction, and methods to assess predictive model quality. The later chapters describe the application of quantitative approaches to describing and optimising potency, selectivity, drug metabolism and pharmacokinetic properties and toxicology, and the design of chemical libraries to feed the screening approaches to lead generation that underpin modern drug discovery. Finally the book describes the impact of bioinformatics, current status of predicting ligand affinity direct from the protein structure, and the application of quantitative approaches to predicting environmental risk. The book provides a summary of the current state-of-the-art in quantitative approaches to drug design, and future opportunities, but it also provides inspiration to drug design practitioners to apply careful design, to make best use of the quantitative methods that are available, while continuing to improve them. Drug discovery still relies heavily on random screening and empirical screening cascades to identify leads and drugs and the process has many failures to deliver only a small handful of drugs. With the rapidly escalating costs of drug discovery and development together with spiralling delivery, quantitative approaches hold the promise of shifting the balance of success, to enable drug discovery to maintain its economic viability.
Drug Design Strategies: Quantitative Approaches, The Royal Society of Chemistry, 2011.
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Table of contents
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The Evolution of Quantitative Drug Designp1-34ByKeith JamesKeith JamesThe Scripps Research Institute10550 N. Torrey Pines Road,BCC-483, La Jolla, CA 92014USASearch for other works by this author on:
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Chapter 2: Drug-Like Physicochemical Propertiesp35-59ByPaul D. Leeson;Paul D. LeesonAstraZeneca R&D CharnwoodBakewell Road, Loughborough, Leics., LE11 5RHUKSearch for other works by this author on:Tudor I. OpreaTudor I. OpreaDivision of BiocomputingDepartment of Biochemistry and Molecular Biology and University of New Mexico (UNM) Center for Molecular Discovery, UNM School of Medicine, MSC11 6145, Albuquerque, New Mexico 87131USASearch for other works by this author on:
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Chapter 3: Development of QSARp60-87ByYvonne Connolly MartinYvonne Connolly MartinMartin Consulting2230 Chestnut St., Waukegan IL 60087USASearch for other works by this author on:
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Chapter 4: The Development of Molecular Modelling Programs: The Use and Limitations of Physical Modelsp88-107ByRichard A. LewisRichard A. LewisComputer-aided Drug DiscoveryNovartis Institutes for Biomedical Research, CH-4002, BaselSwitzerlandSearch for other works by this author on:
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Chapter 5: Contribution of Structure-Based Drug Design to the Discovery of Marketed drugsp108-163ByAlexander A. Alex;Alexander A. AlexPfizer Global Research and DevelopmentRamsgate Road, Sandwich CT13 9NJUKSearch for other works by this author on:David S. MillanDavid S. MillanPfizer Global Research and DevelopmentRamsgate Road, Sandwich CT13 9NJUKSearch for other works by this author on:
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Chapter 6: Representing Chemical Structures in Databases for Drug Designp164-191ByJohn M. Barnard;John M. BarnardDigital Chemistry Ltd.30 Kiveton Lane, Todwick, Sheffield, S26 1HLUKSearch for other works by this author on:Paul N. WallacePaul N. WallaceGlaxoSmithKlineGunnels Wood Road, Stevenage, Herts, SG1 2NYUKSearch for other works by this author on:
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Chapter 7: Modeling Chemical Structure-Log Pp192-219ByRajeshwar P. Verma;Rajeshwar P. VermaPomona CollegeDepartment of Chemistry, 645 North College Avenue, Claremont, California 91711USASearch for other works by this author on:Cynthia D. Selassie;Cynthia D. SelassiePomona CollegeDepartment of Chemistry, 645 North College Avenue, Claremont, California 91711USASearch for other works by this author on:Albert J. LeoAlbert J. LeoBioByte Corporation201 West 4th St., #204, Claremont, California 91711USASearch for other works by this author on:
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Chapter 8: Characterising Chemical Structure Using Physicochemical Descriptorsp220-241ByDavid J. LivingstoneDavid J. LivingstoneChemQuestSandown, Isle of Wight, UK and Centre for Molecular Design, University of Portsmouth, PortsmouthUKSearch for other works by this author on:
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Chapter 9: Assessing Quantitative Model Quality and Performancep242-266ByAndrew M. DavisAndrew M. DavisAstraZeneca Respiratory and Inflammation Innovative MedicinesPepparedsleden 1, 431 50 MölndalSwedenSearch for other works by this author on:
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Chapter 10: Application of Modelling Techniquesp267-278ByDavid E. LeahyDavid E. LeahyMolplex Ltdi6, Charlotte Square, Newcastle Upon TyneUKSearch for other works by this author on:
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Chapter 11: Expert Systems: The Use of Expert Systems in Drug Design-Toxicity and Metabolismp279-311ByAnthony Long;Anthony LongLhasa Limited22-23 Blenheim Terrace, Woodhouse Lane, Leeds, West Yorkshire, LS2 9HDUKSearch for other works by this author on:Kristina Fielding;Kristina FieldingLhasa Limited22-23 Blenheim Terrace, Woodhouse Lane, Leeds, West Yorkshire, LS2 9HDUKSearch for other works by this author on:Nicole McSweeney;Nicole McSweeneyLhasa Limited22-23 Blenheim Terrace, Woodhouse Lane, Leeds, West Yorkshire, LS2 9HDUKSearch for other works by this author on:Martin Payne;Martin PayneLhasa Limited22-23 Blenheim Terrace, Woodhouse Lane, Leeds, West Yorkshire, LS2 9HDUKSearch for other works by this author on:Ella SmoraczewskaElla SmoraczewskaLhasa Limited22-23 Blenheim Terrace, Woodhouse Lane, Leeds, West Yorkshire, LS2 9HDUKSearch for other works by this author on:
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Chapter 12: Ligand-Based Modeling of Toxicityp312-344BySean Ekins;Sean EkinsCollaborations in Chemistry, 5616 Hilltop Needmore RoadFuquay-Varina, NC 27526USADepartment of Pharmaceutical Sciences University of MarylandMD 21201USADepartment of Pharmacology University of Medicine & Dentistry of New Jersey (UMDNJ)-Robert Wood Johnson Medical School675 Hoes Lane, Piscataway, NJ 08854USASearch for other works by this author on:Sandhya Kortagere;Sandhya KortagereDepartment of Microbiology and Immunology, Drexel University College of MedicinePhiladelphia, PA 19129USASearch for other works by this author on:Matthew D. Krasowski;Matthew D. KrasowskiDepartment of Pathology, University of Iowa Hospitals and ClinicsIowa City, IA, 52242USASearch for other works by this author on:Antony J. Williams;Antony J. WilliamsRoyal Society of Chemistry, 904 Tamaras CircleWake Forest, NC-27587USA. (AJW)Search for other works by this author on:Jinghai James Xu;Jinghai James XuKnowledge Discovery and Knowledge Management (KDKM), Merck & Co.Inc., 126 E. Lincoln Ave, Rahway, NJ 07065USA. (JJX)Search for other works by this author on:Michael ZientekMichael ZientekPfizer Global Research & Development PharmacokineticsDynamics & Drug Metabolism, San Diego CAUSASearch for other works by this author on:
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Chapter 13: ADME(T) Predictions in Drug Discoveryp345-366ByAndrew M. Davis;Andrew M. DavisAstraZeneca Respiratory and Inflammation Innovative MedicinesPepparedsleden 1, 43 150 MölndalSwedenSearch for other works by this author on:Robert J. RileyRobert J. RileyAstraZeneca New Opportunities Innovative MedicinesAlderley Park, Macclesfield, CheshireUK, SK10 4TGSearch for other works by this author on:
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Chapter 14: Design of Chemical Librariesp367-396ByDarren V. S. GreenDarren V. S. GreenGlaxoSmithKline R&DDepartment of Computational and Structural Chemistry, Gunnels Wood Road, Stevenage SG1 2NYUKSearch for other works by this author on:
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Chapter 15: The Impact of Genomics, Systems Biology, and Bioinformatics on Drug and Target Discovery: Challenge and Opportunityp397-439ByDarren R. FlowerDarren R. FlowerLife and Health SciencesAston University, Aston Triangle, Birmingham, B5 7ETUnited Kingdom,Search for other works by this author on:
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Chapter 16: Scoring Drug-Receptor Interactionsp440-457ByGregory L. Warren;Gregory L. WarrenOpenEye Scientific SoftwareInc., 9 Bisbee Court Suite D, Santa Fe, NM 87508USASearch for other works by this author on:Stephen D. WarrenStephen D. WarrenDepartment of Chemistry & BiochemistryGonzaga University, 502 E Boone Ave, Spokane, WA 99258USASearch for other works by this author on:
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Chapter 17: Modelling Chemicals in the Environmentp458-478ByPaola GramaticaPaola GramaticaInsubria UniversityDepartment of Structural and Functional Biology, Via Dunant 3, 21100, VareseItalySearch for other works by this author on:
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