Young David C. Computational Drug Design: A Guide for Computational and Medicinal Chemists

John Wiley & Sons, Inc. 2009. — 307 p.For students interested in pursuing a career in the drug design field, this text is intended to give an ideal starting point for their studies. The text assumes a solid background in chemistry, a basic understanding of biochemistry, and nly minimal previous exposure to computational chemistry.
Researchers already employed in the drug design field will be particularly nterested in the tables comparing accuracies of docking methods. There is also a fairly large table of bioisosteric substitutions. Providing an overview of the whole field may turn out to be this book’s greatest contribution.Symbols used in this book
Book abstractA Difficult Problem
An Expensive Problem
Where Computational Techniques are UsedPart I The drug design process

Properties that Make a Molecule a Good DrugCompound Testing
Biochemical Assays
Cell-Based Assays
Animal Testing
Human Clinical Trials
Molecular Structure
Activity
Bioavailability and Toxicity
Drug Side Effects
Multiple Drug Interactions
Metrics for Drug-Likeness
Exceptions to the RulesTarget IdentificationPrimary Sequence and Metabolic Pathway
Crystallography
D NMR
Homology Models
Protein FoldingTarget CharacterizationAnalysis of Target Mechanism
Kinetics and Crystallography
Automated Crevice Detection
Transition Structures and Reaction Coordinates
Molecular Dynamics Simulations
Where the Target is Expressed
Pharmacophore Identification
Choosing an Inhibitor MechanismThe Drug Design Process for a Known Protein TargetThe Structure-Based Design Process
Initial Hits
Compound Refinement
ADMET
Drug ResistanceThe Drug Design Process for an Unknown TargetThe Ligand-Based Design Process
Initial Hits
Compound Refinement
ADMETDrug Design for Other TargetsDNA Binding
RNA as a Target
Allosteric Sites
Receptor Targets
Steroids
Targets inside Cells
Targets within the Central Nervous System
Irreversibly Binding Inhibitors
Upregulating Target ActivityCompound Library DesignTargeted Libraries versus Diverse Libraries
From Fragments versus from Reactions
Non-Enumerative Techniques
Drug-Likeness and Synthetic Accessibility
Analyzing Chemical Diversity and Spanning known Chemistries
Compound Selection TechniquesPart II Computational tools And techniques

Homology Model BuildingHow much Similarity is Enough?
Steps for Building a Homology Model
Step : Template Identification
Step : Alignment between the Unknown and the Template
Step : Manual Adjustments to the Alignment
Step : Replace Template Side Chains with Model Side Chains
Step : Adjust Model for Insertions and Deletions
Step : Optimization of the Model
Step : Model Validation
Step : If Errors are Found Iterate Back to Previous Steps
Reliability of ResultsMolecular MechanicsA Really Brief Introduction to Molecular Mechanics
Force Fields for Drug DesignProtein FoldingThe Difficulty of the Problem
Algorithms
Reliability of Results
Conformational AnalysisDockingIntroduction
Search Algorithms
Searching the Entire Space
Grid Potentials versus Full Force Field
Flexible Active Sites
Ligands Covalently Bound to the Active Site
Hierarchical Docking Algorithms
Scoring
Energy Expressions and Consensus Scoring
Binding Free Energies
Solvation
Ligands Covalently Bound to the Active Site
Metrics for Goodness of Fit
Validation of Results
Comparison of Existing Search and Scoring Methods
Special Systems
The Docking Process
Protein Preparation
Building the Ligand
Setting the Bounding Box
Docking Options
Running the Docking Calculation
Analysis of ResultsPharmacophore ModelsComponents of a Pharmacophore Model
Creating a Pharmacophore Model from Active Compounds
Creating a Pharmacophore Model from the Active Site
Searching Compound Databases
Reliability of ResultsQSARConventional QSAR versus D-QSAR
The QSAR Process
Descriptors
Automated QSAR Programs
QSAR versus Other Fitting MethodsD-QSARThe D-QSAR Process
D-QSAR Software PackagesQuantum Mechanics in Drug DesignQuantum Mechanics Algorithms and Software
Modeling Systems with Metal Atoms
Increased Accuracy
Computing Reaction Paths
Computing SpectraDe novo and Other AI TechniquesDe novo Building of Compounds
Nonquantitative Predictions
Quantitative PredictionsCheminformaticsSmiles SLN and Other Chemical Structure Representations
Similarity and Substructure Searching
D-to-D Structure Generation
Clustering Algorithms
Screening Results Analysis
Database SystemsADMETOral Bioavailability
Drug Half-Life in the Bloodstream
Blood–Brain Barrier Permeability
ToxicityMultiobjective OptimizationAutomation of TasksBuilt-In Automation Capabilities
Automation Using External UtilitiesPart III Related topics

BioinformaticsSimulations at the Cellular and Organ LevelCellular Simulations
Organ SimulationsSynthesis Route PredictionProteomicsProdrug ApproachesFuture Developments in Drug DesignIndividual Patient Genome Sequencing
Analysis of the Entire Proteome
Drugs Customized for Ethnic Group or Individual Patient
Genetic Manipulation
Cloning
Stem Cells
LongevityAppendix: About the CD

Index