PHARMACEUTICAL BIOCHEMISTRY

By ELIZABETH JOHNSON

CONTENTS CHAPTER THE EVOLUTION OF QUANTITATIVE DRUG DESIGN INTRODUCTION A FRAMEWORK FOR INTEGRATED DRUG DESIGN A SIMPLE MODEL DRUG-RELATED DATA TARGET-RELATED DATA DRUG–TARGET COMPLEX-RELATED DATA DRUG DESIGN EVOLUTION DRUG DESIGN QSAR-DRIVEN DRUG DESIGN THE EMERGENCE OF STRUCTURE-BASED DRUG DESIGN PARALLEL MEDICINAL CHEMISTRY THE OMICS ERA DRUG DESIGN IN THE FUTURE REFERENCES CHAPTER DRUG-LIKE PHYSICOCHEMICAL PROPERTIES DRUG-LIKENESS THE IMPACT OF THE RULE OF FIVE ORAL AND NON-ORAL DRUG PROPERTIES ADME PRO?LES AND PHYSICAL PROPERTIES TOXICITY RISKS AND PHYSICAL PROPERTIES DRUGABILITY LEAD-LIKENESS LIGAND E?CIENCY METRICS CONCLUSIONS ACKNOWLEDGEMENTS DEVELOPMENT OF QSAR OVERVIEW OF QSAR THE INVENTION OF QSAR PROPERTIES CALCULATED FROM 2D STRUCTURE OF MOLECULES E?ECTS OF SUBSTITUENTS ON THE ELECTROSTATIC PROPERTIES OF THE PARENT MOLECULE STERIC E?ECTS OF SUBSTITUENTS HYDROPHOBIC PROPERTIES OF MOLECULES 2D DESCRIPTORS FOR HYDROGEN BONDING OTHER MOLECULAR DESCRIPTORS PROPERTIES CALCULATED FROM THE 3D CONFORMATION OF THE MOLECULE SELECTION OF THE CONFORMATION 3D PROPERTY CALCULATION THE RELATIONSHIP BETWEEN CALCULATED 2D AND 3D MOLECULAR PROPERTIES COMPUTATIONAL METHODS TO RELATE MOLECULAR PROPERTIES TO BIOACTIVITY STATISTICAL APPROACHES MACHINE LEARNING AND OTHER NON-STATISTICAL APPROACHES METHODS TO ASSESS THE PREDICTIVITY OF A QSAR THE CONTRAST BETWEEN QSAR AND TRADITIONAL SAR THE FUTURE OF QSAR THE DEVELOPMENT OF MOLECULAR MODELLING PROGRAMS: THE USE AND LIMITATIONS OF PHYSICAL MODELS THE USE AND LIMITATIONS OF PHYSICAL MODELS DEVELOPMENT OF MOLECULAR MECHANICS AND QUANTUM MECHANICS QUANTUM MECHANICS MOLECULAR REPRESENTATIONS PHARMACOPHORES CONFORMATIONAL ANALYSIS AND GLOBAL ENERGY MINIMA PREDICTION MOLECULAR DYNAMICS CALCULATIONS QUANTITATIVE USES OF MODELLING VIRTUAL SCREENING AND RATIONAL DESIGN DOCKING AND SCORING MODELLING OF WATER IMPACT OF THE ADVENT OF A?ORDABLE COMPUTING CASE STUDIES SHOWING THE IMPACT OF MODELLING CONTROL EXPERIMENTS ORAL BIOAVAILABILITY THE HINGE BINDING HYPOTHESIS FOR KINASE INHIBITORS DRUGS DISCOVERED USING MODELLING FUTURE DEVELOPMENTS SOCIOLOGY OF DATA PRESENTATION AND INTERPRETATION DOMAIN OF APPLICABILITY CONTRIBUTION OF STRUCTURE-BASED DRUG DESIGN TO THE DISCOVERY OF MARKETED DRUGS EXPERIMENTAL METHODS IN STRUCTURE-BASED DRUG DESIGN OPPORTUNITIES AND LIMITATIONS FOR X-RAY CRYSTALLOGRAPHY OPPORTUNITIES AND LIMITATIONS FOR NUCLEAR MAGNETIC RESONANCE OPPORTUNITIES AND LIMITATIONS FOR ISOTHERMAL TITRATION CALORIMETRY ENERGETICS OF MOLECULAR INTERACTIONS IN PROTEIN–LIGAND COMPLEXES EXAMPLES OF STRUCTURE-BASED DRUG DESIGN IN THE DISCOVERY OF MARKETED DRUGS AND ADVANCED CLINICAL CANDIDATES ANGIOTENSIN-CONVERTING ENZYME INHIBITOR AS A DRUG FOR THE TREATMENT OF HYPERTENSION: CAPTOPRIL CARBONIC ANHYDRASE INHIBITORS DORZOLAMIDE AND BRINZOLAMIDE AS DRUGS FOR THE TREATMENT OF GLAUCOMA HIV PROTEASE INHIBITORS SAQUINAVIR, RITONAVIR, INDINAVIR, NEL?NAVIR, AMPRENAVIR, LOPINAVIR, ATAZANAVIR, FOSAMPRENAVIR, TIPRANAVIR AND DARUNAVIR AS DRUGS AGAINST HIV INFECTION NON-PEPTIDIC HIV PROTEASE INHIBITOR, TIPRANAVIR AS A DRUG FOR THE TREATMENT OF HIV NUCLEOSIDE ANALOGUE HIV REVERSE TRANSCRIPTASE INHIBITORS AS DRUGS FOR THE TREATMENT OF HIV AND HEPATITIS B: ZIDOVUDINE, DIDANOSINE, STAVUDINE, LAMIVUDINE, ABACAVIR, EMTRICITABINE AND ENTECAVIR NON-NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITOR AS DRUGS FOR THE TREATMENT OF HIV: EFAVIRENZ, NEVIRAPINE, DELAVIRDINE, APRICITABINE AND ETRAVIRINE THROMBIN INHIBITORS MELAGATRAN/XIMELAGA- TRAN AND DABIGATRAN AS DRUGS FOR THE TREATMENT OF THROMBOEMBOLYTIC DISEASE INHIBITORS OF FACTOR X AS DRUGS FOR THE TREATMENT OF THROMBOEMBOLYTIC DISEASE: RIVAROXABAN AND APIXABAN RENIN INHIBITOR ALISKIREN AS DRUG FOR THE TREATMENT OF HYPERTENSION ABL KINASE INHIBITORS IMATINIB, NILOTINIB AND DASATINIB AS DRUGS FOR THE TREATMENT OF CHRONIC MYELOID LEUKEMIA IN?UENZA NEURAMINIDASE INHIBITORS ZANAMIVIR AND OSELTAMIVIR AS DRUGS FOR THE TREATMENT OF IN?UENZA HAS STRUCTURE-BASED DRUG DESIGN INCREASED THE SPEED AND PRODUCTVITY OF DRUG DISCOVERY? A MEDICINAL CHEMIST’S PERSPECTIVE OUTLOOK REPRESENTING CHEMICAL STRUCTURES IN DATABASES FOR DRUG DESIGN COMPUTER REPRESENTATION OF CHEMICAL STRUCTURES TOPOLOGICAL GRAPHS STRUCTURE DIAGRAMS CHEMICAL NOMENCLATURE LINE NOTATIONS CONNECTION TABLES IUPAC INTERNATIONAL CHEMICAL IDENTI?ER (INCHI) STEREOCHEMISTRY THREE-DIMENSIONAL STRUCTURE REPRESENTATION FRAGMENT CODES AND STRUCTURE FINGERPRINTS MARKUSH STRUCTURES CANONICALISATION AND NORMALISATION CANONICALISATION NORMALISATION AND BUSINESS RULES PHYSIOLOGICALLY RELEVANT FORMS REGISTRATION SYSTEMS PARENT/VERSION/PREPARATION HIERARCHY MIXTURES STRUCTURAL UNCERTAINTY UNKNOWN STRUCTURES ANALYSIS OF STRUCTURAL DATABASES CLUSTERING AND SUBSETTING R-GROUP DECOMPOSITION REDUCED REPRESENTATIONS MATCHED MOLECULAR PAIR ANALYSIS CONCLUSIONS AND FUTURE DIRECTIONS MODELING CHEMICAL STRUCTURE-LOG P GENERAL HAMMETT APPROACH STERIC CONSTANTS HYDROPHOBICITY AND BIOLOGICAL ACTIVITY DIRECT MEASUREMENT OF PARTITION COE?CIENTS SHAKE-FLASK METHOD POTENTIOMETRIC TITRATION METHOD HIGH THROUGHPUT SCREENING (HTS) METHOD INDIRECT METHODS FOR DETERMINATION OF PARTITION COE?CIENTS REVERSED PHASE THIN-LAYER CHROMATOGRAPHY REVERSED PHASE HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY ARTI?CIAL MEMBRANE CHROMATOGRAPHIC METHOD ELECTROKINETIC CHROMATOGRAPHIC METHODS HYDROPHOBICITY AND ITS CALCULATION CLOGP-RULES OF ENGAGEMENT HYDROPHOBICITY AND ITS APPLICATIONS HYDROPHOBICITY AND CENTRAL NERVOUS SYSTEM TOXICITY HYDROPHOBICITY AND ABSORPTION INHIBITION HYDROPHOBICITY AND TOXICITY: MUTAGENICITY AND CARCINOGENICITY HYDROPHOBICITY AND TOXICITY: HERG BLOCKAGE HYDROPHOBICITY AND BIOACCUMULATION CONCLUSION CHARACTERISING CHEMICAL STRUCTURE USING PHYSICOCHEMICAL DESCRIPTORS PHYSICAL ORGANIC CHEMISTRY ELECTRONIC PROPERTIES HYDROPHOBIC PROPERTIES STERIC PROPERTIES TOPOLOGICAL DESCRIPTORS EXPERIMENTAL PARAMETERS FROM MOLECULAR MODELLING/ COMPUTATIONAL CHEMISTRY 1D, 2D AND 3D DESCRIPTORS AND CONFORMATION MOLECULAR FIELDS FINGERPRINTS WHICH ARE THE BEST PROPERTIES TO USE? ASSESSING QUANTITATIVE MODEL QUALITY AND PERFORMANCE PHYSICS-BASED AND EMPIRICAL MODELS OECD GUIDELINES ON QSAR MODEL GENERATION AND VALIDATION GOODNESS OF ?T PEARSONS PRODUCT MOMENT CORRELATION COE?CIENT (R) THE PROBLEM OF USING R/R2 TO COMPARE MODELS THE USE OF ROOT MEAN SQUARE ERROR IN FIT AND PREDICTION MODEL ROBUSTNESS PARAMETRIC STATISTICS IN LINEAR AND MULTIPLE REGRESSION Q2 AND Q2 STATISTIC Y-RANDOMISATION ASSESSMENT OF PREDICTIVITY CALCULATION OF Q2 USING AN EXTERNAL TEST SET USE OF A TEMPORAL TEST SET CLASSI?ED DATASETS COOPER STATISTICS PREVALENCE IN CLASSI?ED DATASETS CLASSI?CATION OF PREDICTIONS FROM CONTINUOUS MODELS RECEIVER OPERATING CHARACTERISTIC CURVES STATISTICAL VS PRACTICAL SIGNI?CANCE IN PREDICTION FUTURE OUTLOOK XIII CHAPTER 10 APPLICATION OF MODELLING TECHNIQUES QUANTITATIVE MODELLING METHODS OVERVIEW KNOWLEDGE REPRESENTATIONS DATA MINING SURVEY META-MODEL APPLICATION CHAPTER 11 EXPERT SYSTEMS: THE USE OF EXPERT SYSTEMS IN DRUG DESIGN-TOXICITY AND METABOLISM A DESCRIPTION OF DEREK FOR WINDOWS RAPID PROTOTYPE ALERTS APPLICABILITY DOMAINS A DESCRIPTION OF METEOR INTEGRATION OF METEOR WITH OTHER PROGRAMS THE EXPERT SYSTEM FOR TOXICITY PREDICTION IN DRUG DESIGN AND DISCOVERY STORAGE OF TOXICOLOGICAL KNOWLEDGE LEAD IDENTI?CATION LEAD OPTIMISATION PRE-CLINICAL AND CLINICAL STAGES OCCUPATIONAL HEALTH ASSESSMENT ENVIRONMENTAL SAFETY SUPPORT OF REGULATORY APPLICATIONS THE USE OF EXPERT SYSTEMS TO ASSESS GENOTOXIC IMPURITIES THE EXPERT SYSTEM FOR METABOLISM PREDICTION IN DRUG DESIGN AND DISCOVERY METEOR AND THE ‘METABOLITES IN SAFETY TESTING’ GUIDELINES THE USE OF METEOR TO ACCELERATE METABOLITE IDENTI?CATION CONCLUSION AND FUTURE PERSPECTIVES CHAPTER 12 LIGAND-BASED MODELING OF TOXICITY HERG HERG PHARMACOPHORES HERG CLASSI?CATION METHODS QSAR FOR DRUG METABOLIZING ENZYMES PHARMACOPHORES FOR P450S METABOLIC STABILITY MODELS P450 3A4 METABOLIC INTERMEDIATE COMPLEX FORMATION AND TIME DEPENDENT INHIBITION PREGANE X RECEPTOR MODELS DRUG INDUCED LIVER INJURY MODELS FROM LIGANDS TO PHARMACOPHORES TO NETWORKS TO UNDERSTAND TOXICITY DISCUSSION CHAPTER 13 ADME(T) PREDICTIONS IN DRUG DISCOVERY PREDICTING HUMAN ABSORPTION THE BIOPHARMACEUTICS CLASSI?CATION SYSTEM THE ACAT MODEL THE BIOPHARMACEUTICS DRUG DISPOSITION CLASSI?CATION SYSTEM PREDICTING HUMAN DRUG DISTRIBUTION PREDICTING HUMAN HEPATIC THE WELL-STIRRED MODEL PHYSIOLOGICALLY BASED PHARMACOKINETIC MODELS ALLOMETRY PREDICTING OTHER HUMAN CLEARANCE MECHANISMS PREDICTING HUMAN BIOAVAILABILITY PREDICTING HUMAN DOSE AND DOSE FREQUENCY PREDICTING DRUG–DRUG INTERACTIONS PHYSICO-CHEMICAL CONTROL CONCLUSIONS AND FUTURE OUTLOOK CHAPTER 14 DESIGN OF CHEMICAL LIBRARIES SIMILARITY METHODS DIVERSITY METHODS PROTEIN FAMILY APPROACHES BEYOND SIMPLE DIVERSITY COMBINATORIAL DESIGN COMPOUND COLLECTION ENHANCEMENT WORK?OWS SCREENING LIBRARY DESIGN OTHER CONSIDERATIONS DIVERSITY TARGET FAMILIES FOCUSSED SCREENING CHAPTER 15 THE IMPACT OF GENOMICS, SYSTEMS BIOLOGY, AND BIOINFORMATICS ON DRUG AND TARGET DISCOVERY: CHALLENGE AND OPPORTUNITY GENOMICS AND ITS INHERITORS AN EXPLOSION OF -OMES DRUG DISCOVERY TECHNOLOGY AND GENOMICS TARGET DISCOVERY IN THE GENOMIC ERA TRANSCRIPTOMICS AND MICROARRAYS PROTEOMICS AND MASS SPECTROMETRY BIOINFORMATICS STRUCTURAL GENOMICS AND FRAGMENT-BASED DRUG DISCOVERY COMPUTATIONAL BIOSCIENCE AND SYSTEMS BIOLOGY NEW KINDS OF DRUG DRUGGING PROTEIN–PROTEIN INTERACTIONS SYSTEMS BIOLOGY AND POLYPHARMACOLOGY REPURPOSING BIOLOGICS AND VACCINES PHARMACOGENOMICS AND PERSONAL MEDICINES CHAPTER 16 SCORING DRUG-RECEPTOR INTERACTIONS DOCKING – WHAT WORKS? BINDING MODE PREDICTION VIRTUAL SCREENING PREDICTING LIGAND A?NITY QSAR EMPIRICAL METHODS PHYSICS-BASED METHODS ANOTHER MATTER CHAPTER 17 MODELLING CHEMICALS IN THE ENVIRONMENT LACK OF PHYSICO-CHEMICAL AND TOXICITY DATA FOR CHEMICALS IN THE ENVIRONMENT THE NEED FOR THE NEW LEGISLATION FOR CHEMICALS: REACH OECD PRINCIPLES FOR THE VALIDATION, FOR REGULATORY PURPOSES, OF (Q)SAR MODELS A DE?NED ENDPOINT AN UNAMBIGUOUS ALGORITHM A DE?NED DOMAIN OF APPLICABILITY APPROPRIATE MEASURES OF GOODNESS-OF-FIT, ROBUSTNESS AND PREDICTIVITY A MECHANISTIC INTERPRETATION, IF POSSIBLE MODELS FOR CUMULATIVE END-POINTS (POPS, PBTS, ETC ): UTILITY FOR THE SCREENING, PRIORITIZATION AND FOR THE DESIGN OF SAFER ALTERNATIVE CHEMICALS