COMPUTATIONAL DRUG DESIGN -- CONTENTS -- PREFACE -- ACKNOWLEDGMENTS -- ABOUT THE AUTHOR -- SYMBOLS USED IN THIS BOOK -- BOOK ABSTRACT -- 1 Introduction -- 1.1 A Difficult Problem -- 1.2 An Expensive Problem -- 1.3 Where Computational Techniques are Used -- Bibliography -- PART I THE DRUG DESIGN PROCESS -- 2 Properties that Make a Molecule a Good Drug -- 2.1 Compound Testing -- 2.1.1 Biochemical Assays -- 2.1.2 Cell-Based Assays -- 2.1.3 Animal Testing -- 2.1.4 Human Clinical Trials -- 2.2 Molecular Structure -- 2.2.1 Activity -- 2.2.2 Bioavailability and Toxicity -- 2.2.3 Drug Side Effects -- 2.2.4 Multiple Drug Interactions -- 2.3 Metrics for Drug-Likeness -- 2.4 Exceptions to the Rules -- Bibliography -- 3 Target Identification -- 3.1 Primary Sequence and Metabolic Pathway -- 3.2 Crystallography -- 3.3 2D NMR -- 3.4 Homology Models -- 3.5 Protein Folding -- Bibliography -- 4 Target Characterization -- 4.1 Analysis of Target Mechanism -- 4.1.1 Kinetics and Crystallography -- 4.1.2 Automated Crevice Detection -- 4.1.3 Transition Structures and Reaction Coordinates -- 4.1.4 Molecular Dynamics Simulations -- 4.2 Where the Target is Expressed -- 4.3 Pharmacophore Identification -- 4.4 Choosing an Inhibitor Mechanism -- Bibliography -- 5 The Drug Design Process for a Known Protein Target -- 5.1 The Structure-Based Design Process -- 5.2 Initial Hits -- 5.3 Compound Refinement -- 5.4 ADMET -- 5.5 Drug Resistance -- Bibliography -- 6 The Drug Design Process for an Unknown Target -- 6.1 The Ligand-Based Design Process -- 6.2 Initial Hits -- 6.3 Compound Refinement -- 6.4 ADMET -- Bibliography -- 7 Drug Design for Other Targets -- 7.1 DNA Binding -- 7.2 RNA as a Target -- 7.3 Allosteric Sites -- 7.4 Receptor Targets -- 7.5 Steroids -- 7.6 Targets inside Cells -- 7.7 Targets within the Central Nervous System -- 7.8 Irreversibly Binding Inhibitors.

7.9 Upregulating Target Activity -- Bibliography -- 8 Compound Library Design -- 8.1 Targeted Libraries versus Diverse Libraries -- 8.2 From Fragments versus from Reactions -- 8.3 Non-Enumerative Techniques -- 8.4 Drug-Likeness and Synthetic Accessibility -- 8.5 Analyzing Chemical Diversity and Spanning known Chemistries -- 8.6 Compound Selection Techniques -- Bibliography -- PART II COMPUTATIONAL TOOLS AND TECHNIQUES -- 9 Homology Model Building -- 9.1 How much Similarity is Enough? -- 9.2 Steps for Building a Homology Model -- 9.2.1 Step 1: Template Identification -- 9.2.2 Step 2: Alignment between the Unknown and the Template -- 9.2.3 Step 3: Manual Adjustments to the Alignment -- 9.2.4 Step 4: Replace Template Side Chains with Model Side Chains -- 9.2.5 Step 5: Adjust Model for Insertions and Deletions -- 9.2.6 Step 6: Optimization of the Model -- 9.2.7 Step 7: Model Validation -- 9.2.8 Step 8: If Errors are Found, Iterate Back to Previous Steps -- 9.3 Reliability of Results -- Bibliography -- 10 Molecular Mechanics -- 10.1 A Really Brief Introduction to Molecular Mechanics -- 10.2 Force Fields for Drug Design -- Bibliography -- 11 Protein Folding -- 11.1 The Difficulty of the Problem -- 11.2 Algorithms -- 11.3 Reliability of Results -- 11.4 Conformational Analysis -- Bibliography -- 12 Docking -- 12.1 Introduction -- 12.2 Search Algorithms -- 12.2.1 Searching the Entire Space -- 12.2.2 Grid Potentials versus Full Force Field -- 12.2.3 Flexible Active Sites -- 12.2.4 Ligands Covalently Bound to the Active Site -- 12.2.5 Hierarchical Docking Algorithms -- 12.3 Scoring -- 12.3.1 Energy Expressions and Consensus Scoring -- 12.3.2 Binding Free Energies -- 12.3.3 Solvation -- 12.3.4 Ligands Covalently Bound to the Active Site -- 12.3.5 Metrics for Goodness of Fit -- 12.4 Validation of Results -- 12.5 Comparison of Existing Search and Scoring Methods.

12.6 Special Systems -- 12.7 The Docking Process -- 12.7.1 Protein Preparation -- 12.7.2 Building the Ligand -- 12.7.3 Setting the Bounding Box -- 12.7.4 Docking Options -- 12.7.5 Running the Docking Calculation -- 12.7.6 Analysis of Results -- Bibliography -- 13 Pharmacophore Models -- 13.1 Components of a Pharmacophore Model -- 13.2 Creating a Pharmacophore Model from Active Compounds -- 13.3 Creating a Pharmacophore Model from the Active Site -- 13.4 Searching Compound Databases -- 13.5 Reliability of Results -- Bibliography -- 14 QSAR -- 14.1 Conventional QSAR versus 3D-QSAR -- 14.2 The QSAR Process -- 14.3 Descriptors -- 14.4 Automated QSAR Programs -- 14.5 QSAR versus Other Fitting Methods -- Bibliography -- 15 3D-QSAR -- 15.1 The 3D-QSAR Process -- 15.2 3D-QSAR Software Packages -- 15.3 Summary -- Bibliography -- 16 Quantum Mechanics in Drug Design -- 16.1 Quantum Mechanics Algorithms and Software -- 16.2 Modeling Systems with Metal Atoms -- 16.3 Increased Accuracy -- 16.4 Computing Reaction Paths -- 16.5 Computing Spectra -- Bibliography -- 17 De novo and Other AI Techniques -- 17.1 De novo Building of Compounds -- 17.2 Nonquantitative Predictions -- 17.3 Quantitative Predictions -- Bibliography -- 18 Cheminformatics -- 18.1 Smiles, SLN, and Other Chemical Structure Representations -- 18.2 Similarity and Substructure Searching -- 18.3 2D-to-3D Structure Generation -- 18.4 Clustering Algorithms -- 18.5 Screening Results Analysis -- 18.6 Database Systems -- Bibliography -- 19 ADMET -- 19.1 Oral Bioavailability -- 19.2 Drug Half-Life in the Bloodstream -- 19.3 Blood-Brain Barrier Permeability -- 19.4 Toxicity -- Bibliography -- 20 Multiobjective Optimization -- Bibliography -- 21 Automation of Tasks -- 21.1 Built-In Automation Capabilities -- 21.2 Automation Using External Utilities -- Bibliography -- PART III RELATED TOPICS -- 22 Bioinformatics.

Bibliography -- 23 Simulations at the Cellular and Organ Level -- 23.1 Cellular Simulations -- 23.2 Organ Simulations -- Bibliography -- 24 Synthesis Route Prediction -- Bibliography -- 25 Proteomics -- Bibliography -- 26 Prodrug Approaches -- Bibliography -- 27 Future Developments in Drug Design -- 27.1 Individual Patient Genome Sequencing -- 27.2 Analysis of the Entire Proteome -- 27.3 Drugs Customized for Ethnic Group or Individual Patient -- 27.4 Genetic Manipulation -- 27.5 Cloning -- 27.6 Stem Cells -- 27.7 Longevity -- Bibliography -- Appendix: About the CD -- GLOSSARY -- INDEX.