Drug discovery strategies and methods 2004 makriyannis biegel

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Drug discovery strategies and methods 2004   makriyannis  biegel

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... Cannabinergics: Old and New Possibilities Andreas Goutopoulos and Alexandros Makriyannis Development of PET and SPECT Radioligands for Cannabinoid Receptors S John Gatley, Andrew N Gifford, Yu-Shin... areas of research and will provide a contemporary picture of the overall field of drug discovery to scientists from diverse disciplines Alexandros Makriyannis Diane Biegel Copyright 2004 by Marcel... structure-based drug design has become an integral part of the modern drug discovery process and has begun to contribute to a significant portion of the current drug discovery portfolio Copyright 2004 by

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  • dke151_fm.pdf

    • DRUG DISCOVERY STRATEGIES AND METHODS

      • PREFACE

      • CONTENTS

      • CONTRIBUTORS

  • dke151_ch1.pdf

    • DRUG DISCOVERY STRATEGIES & METHODS

      • CHAPTER 1: PROTEIN CRYSTALLOGRAPHY IN STRUCTURE-BASED DRUG DESIGN

        • I. INTRODUCTION

        • II. THE DRUG DISCOVERY PROCESS

        • III. THE STRUCTURE-BASED DRUG DESIGN CYCLE

        • IV. PROTEIN CRYSTALLOGRAPHY

          • A. CRYSTALLIZATION

          • B. X-RAY DIFFRACTION DATA ACQUISITION

          • C. PHASING

          • D. MODEL BUILDING AND REFINEMENT

          • E. UNDERSTANDING STRUCTURAL COORDINATES

        • V. IN SILICO LEAD GENERATION

          • A. IN SILICO SCREENING OF VIRTUAL COMPOUND LIBRARIES

          • B. BUILDING LEADS FROM MOLECULAR FRAGMENTS

        • VI. STRUCTURE-BASED LEAD OPTIMIZATION

        • VII. EXPERIENCE WITH STRUCTURE-BASED DRUG DESIGN

          • A. DESIGN SHOULD BE BASED ON LIGANDED STRUCTURES

          • B. DESIGN OF SMALL MOLECULES TO INTERFERE WITH PROTEIN–PROTEIN INTERACTION REQUIRES THE STRUCTURE OF THE COMPLEX

          • C. ALLOW FOR FLEXIBILITY IN THE DESIGN OF ENZYME INHIBITORS TO ASSURE OPTIMAL FIT IN AN OFTEN RIGID ACTIVE SITE CAVITY

          • D. SYNTHETIC ACCESSIBILITY IS ESSENTIAL

          • E. EVERY WATER MOLECULE IS SPECIAL

          • F. FILL AVAILABLE SPACE AND MAXIMIZE INTERACTIONS

          • G. BEWARE OF CRYSTAL CONTACTS

          • H. USE OF SURROGATE ENZYMES CAN LEAD TO IMPORTANT INSIGHTS, BUT OPTIMIZATION REQUIRES THE TARGET PROTEIN

          • I. ITERATIVE DESIGN IS ESSENTIAL

          • J. SOLUBILITY OF LIGANDS MATTERS

          • K. NO SUBSTITUTE FOR EXPERIENCE

          • L. DEDICATED MOLECULAR BIOLOGY AND PROTEIN PURIFICATION GROUPS ARE ESSENTIAL

        • VIII. OUTLOOK

        • REFERENCES

  • dke151_ch2.pdf

    • DRUG DISCOVERY STRATEGIES & METHODS

      • Chapter 2: SRC HOMOLOGY-2 DOMAINS AND STRUCTURE- BASED, SMALL- MOLECULE LIBRARY APPROACHES TO DRUG DISCOVERY

        • I. SIGNAL TRANSDUCTION AND PROTEIN–PROTEIN INTERACTIONS

        • II. SRC TYROSINE KINASE AND OSTEOPOROSIS

        • III. SH2 DOMAINS AND PHOSPHOPEPTIDE BINDING

        • IV. LEAD DISCOVERY AND COMBINATORIAL CHEMISTRY

        • V. SOLID-PHASE PARALLEL SYNTHESIS AND NONPEPTIDE PHENYL PHOSPHATE LIBRARIES

        • VI. STRUCTURE-BASED, SMALL-MOLECULE LIBRARIES TO EXPLORE SRC SH2 BINDING

        • VII. DISCOVERY OF AN IN VIVO EFFECTIVE SRC SH2 INHIBITOR

        • VIII. CONCLUSION

        • ACKNOWLEDGMENTS

        • REFERENCES

  • dke151_ch3.pdf

    • DRUG DISCOVERY STRATEGIES & METHODS

      • Chapter 3: THREE-DIMENSIONAL STRUCTURE OF THE INHIBITED CATALYTIC DOMAIN OF HUMAN STROMELYSIN- 1 BY HETERONUCLEAR NMR SPECTROSCOPY

        • I. INTRODUCTION

        • II. THE MATRIX METALLOPROTEINASE FAMILY

        • III. ASSIGNMENT OF THE RESONANCES OF THE INHIBITED CATALYTIC DOMAIN OF STROMELYSIN-1

        • IV. ASSIGNMENT OF THE RESONANCES OF THE INHIBITOR AND NOES BETWEEN THE PROTEIN AND THE INHIBITOR

        • V. STRUCTURE CALCULATIONS

        • VI. STRUCTURE OF INHIBITED STROMELYSIN-1

          • A. THE PROTEIN FOLD

          • B. CONFORMATION OF THE INHIBITOR

        • VII. COMPARISON OF INHIBITED STROMELYSIN TO OTHER MMPS

        • VIII. CONCLUSION

        • REFERENCES

  • dke151_ch4.pdf

    • DRUG DISCOVERY STRATEGIES & METHODS

      • Chapter 4: CANNABINERGICS: OLD AND NEW THERAPEUTIC POSSIBILITIES

        • I. INTRODUCTION

        • II. CANNABINOID RECEPTORS

          • A. THE CB1 RECEPTOR

          • B. THE CB2 RECEPTOR

          • C. CANNABINOID RECEPTOR DISTRIBUTION

          • D. CANNABINOIDS AND MEMBRANES

        • III. THE ENDOGENOUS LIGANDS

          • A. ANANDAMIDE PHARMACOLOGY

          • B. ENDOCANNABINOID METABOLISM

        • IV. THE ENDOCANNABINOID SYSTEM

        • V. MAJOR CLASSES OF CANNABINERGIC LIGANDS

          • A. CLASSICAL CANNABINOIDS

          • B. NONCLASSICAL CANNABINOIDS

          • C. AMINOALKYLINDOLES

          • D. ENDOCANNABINOIDS

          • E. 1,5-BIARYLPYRAZOLES

        • VI. THERAPEUTIC POTENTIAL OF CANNABINERGIC AGENTS

          • A. NERVOUS SYSTEM

          • B. IMMUNE SYSTEM

          • C. CARDIOVASCULAR SYSTEM

          • D. REPRODUCTIVE SYSTEM

          • E. EYE

          • F. RESPIRATORY SYSTEM

          • G. GASTROINTESTINAL SYSTEM

        • VII. CONCLUSIONS

        • REFERENCES

  • dke151_ch5.pdf

    • DRUG DISCOVERY STRATEGIES & METHODS

      • CHAPTER 5: DEVELOPMENT OF PET AND SPECT RADIOLIGANDS FOR CANNABINOID RECEPTORS

        • I. INTRODUCTION

        • II. IMAGING THE EFFECTS OF CANNABINOIDS ON METABOLISM AND BLOOD FLOW

        • III. ATTEMPTS TO DEVELOP RADIOLIGANDS

        • IV. ONGOING WORK

        • V. CONCLUSIONS

        • ACKNOWLEDGMENTS

        • REFERENCES

  • dke151_ch6.pdf

    • DRUG DISCOVERY STRATEGIES & METHODS

      • CHAPTER 6: STRUCTURAL AND PHARMACOLOGICAL ASPECTS OF PEPTIDOMIMETICS

        • I. INTRODUCTION

        • II.µ OPIOID AGONISTS

          • A. CYCLIC PEPTIDES WITH µ AGONIST PROPERTIES

          • B. CONFORMATIONAL STUDY OF H-HAT-D-ORN-AIC-GLU-NH2

        • III. OPIOID ANTAGONISTS

          • A. STRUCTURE–ACTIVITY STUDIES OF TIP(P) PEPTIDES

          • B. CONFORMATIONAL STUDIES OF TIP AND TIPP

          • C. EFFECT OF OPIOID ANTAGONISTS ON THE DEVELOPMENT OF MORPHINE TOLERANCE AND DEPENDENCE

        • IV. MIXED AGONIST/ ANTAGONISTS

          • A. PROTOTYPES AND STRUCTURE–ACTIVITY RELATIONSHIPS

          • B. CONFORMATIONAL STUDY OF H-TYR-C[-ORN-2-NAL-DPRO-GLY-]

        • V.AGONISTS

        • VI. CONCLUSIONS

        • ACKNOWLEDGMENTS

        • REFERENCES

  • dke151_ch7.pdf

    • DRUG DISCOVERY STRATEGIES & METHODS

      • CHAPTER 7: LINKERS AND RESINS FOR SOLID-PHASE SYNTHESIS

        • I. INTRODUCTION

        • II. RESINS AND LINKERS FOR CARBOXYLIC ACID GENERATION

        • III. RESINS AND LINKERS FOR GENERATION OF AMIDE FUNCTION

        • IV. RESINS AND LINKERS FOR SUBSTITUTED AMIDE GENERATION

        • V. RESINS AND LINKERS FOR HYDROXYL AND GENERATION OF AMINO FUNCTION

        • VI. RESINS AND LINKERS FOR HYDROXAMIC GENERATION OF ACID FUNCTIONS

        • VII. RESINS AND LINKERS FOR GENERATIONOF SULFONAMIDE, UREA, AND GUANIDINE FUNCTIONS

        • VIII. RESINS AND LINKERS FOR GENERATION OF ALDEHYDE FUNCTIONS

        • IX. RESINS AND LINKERS FOR GENERATION OF OTHER FUNCTIONS

        • X. CONCLUSION

        • APPENDIX A.HANDLES AND DERIVATIZED SOLID SUPPORTS

        • REFERENCES

  • dke151_ch8.pdf

    • DRUG DISCOVERY STRATEGIES & METHODS

      • CHAPTER 8: ALLOSTERIC MODULATION OF G- PROTEIN- COUPLED RECEPTORS: IMPLICATIONS FOR DRUG ACTION

        • I. INTRODUCTION

        • II. DEFINITION OF ‘‘ALLOSTERIC’’: RELATED MODELS

        • III. MUSCARINIC AND ADENOSINE RECEPTORS

          • A. ALLOSTERIC MODULATION ON THE MUSCARINIC RECEPTOR

          • B. ALLOSTERIC MODULATION ON THE ADENOSINE RECEPTOR

        • IV. CONCLUSION

        • ACKNOWLEDGMENTS

        • REFERENCES

  • dke151_ch9.pdf

    • DRUG DISCOVERY STRATEGIES & METHODS

      • CHAPTER 9: PROTEIN MISFOLDING AND NEURODEGENERATIVE DISEASE: THERAPEUTIC OPPORTUNITIES

        • I. DISEASES WITH PROTEIN MISFOLDING

        • II. MECHANISMS OF PROTEIN POLYMERIZATION

        • III. INTERMEDIATES IN FIBRIL FORMATION

        • IV. CELLULAR SYSTEMS AND AMYLOID FIBRILS

        • V. ANIMAL MODELS OF BRAIN DEPOSITION OF INSOLUBLE PROTEINS

        • VI. CLINICAL TRIALS FOR AD TESTING OF POSSIBLE DISEASE-MODIFYING AGENTS

        • REFERENCES

  • dke151_ch10.pdf

    • DRUG DISCOVERY STRATEGIES & METHODS

      • CHAPTER 10: UNCOATING AND ADSORPTION INHIBITORS OF RHINOVIRUS REPLICATION

        • I. INTRODUCTION

        • II. CAPSID BINDING COMPOUNDS

          • A. THE NATURE OF THE BINDING SITE

          • B. ALIPHATIC BRIDGE

          • C. MODELING OF CONFORMATIONALLY RESTRICTED ANALOGUES

        • III. PHENYL STACKING

        • IV. HYDROGEN BONDING

          • A. HRV-14 MODEL DEVELOPMENT

          • B. MODEL DEVELOPMENT BASED ON SMALL-MOLECULE, LOW-ENERGY CONFORMATIONS

          • C. APPLICATION OF MODEL DEVELOPMENT TO DRUG DESIGN

          • D. THE DEVELOPMENT OF A CLINICAL CANDIDATE

        • V. CONCLUSIONS

        • REFERENCES

  • dke151_ch11.pdf

    • DRUG DISCOVERY STRATEGIES & METHODS

      • CHAPTER 11: PROFILES OF PROTOTYPE ANTIVIRAL AGENTS INTERFERING WITH THE INITIAL STAGES OF HIV INFECTION

        • I. INTRODUCTION

        • II. VIRUS ADSORPTION INHIBITORS:POLYANIONIC SUBSTANCES

        • III. VIRUS – CELL FUSION INHIBITORS: LECTINS, ALBUMINS, AND TRITERPENE DERIVATIVES

        • IV. VIRUS UNCOATING INHIBITORS: BICYCLAMS

        • V. REVERSE TRANSCRIPTASE INHIBITORS INTERACTING WITH THE SUBSTRATE BINDING SITE

          • A. DIDEOXYNUCLEOSIDE ANALOGS

          • B. ACYCLIC NUCLEOSIDE PHOSPHONATES

        • VI. REVERSE TRANSCRIPTASE INHIBITORS INTERACTING WITH A NONSUBSTRATE BINDING SITE: NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS

        • VII. CONCLUSION

        • ACKNOWLEDGMENTS

        • REFERENCES

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