This book is an account of current developments in computational chemistry, a new multidisciplinary area of research. Experts in computational chemistry, the editors use and develop techniques for computer-assisted molecular design. The core of the text itself deals with techniques for computer-assisted molecular design. The book is suitable for both beginners and experts. In addition, protocols and software for molecular recognition and the relationship between structure and biological activity of drug molecules are discussed in detail. Each chapter includes a mini-tutorial, as well as discussion of advanced topics. Special Feature: The appendix to this book contains an extensive list of available software for molecular modeling.

Table of Contents:
1. Basis Sets for Ab Initio Molecular Orbital Calculations and Intermolecular Interactions 1 David Feller and Ernest R. Davidson Introduction 1 Some Terminology 4 Gaussian Compared to Exponential Functions 4 Contracted Gaussians 4 Polarization Functions 7 Complete Sets 8 The Basis Set Superposition Error 9 Choosing a Basis Set 10 Molecular Geometries 11 Energy Differences 15 One-Electron Properties 20 In-Depth Discussion 20 Sources of Gaussian Primitives and Contraction Coefficients 20 Even-Tempered Gaussians 21 Well-Tempered Gaussians 22 MINI-/, MIDI-/ and MAXI-/ etc. 26 Still Others 27 Atomic Natural Orbitals 27 Functions for Augmenting Basis Sets 29 Weak Interactions 34 Conclusion 36 References 37 2. Semiempirical Molecular Orbital Methods 45 James J. P. Stewart Introduction 45 History of Semiempirical Methods 46 Complete Neglect of Differential Overlap 47 Complete Neglect of Differential Overlap Version 2 50 Intermediate Neglect of Differential Overlap 51 Neglect of Diatomic Differential Overlap (NDDO) 52 Modified Neglect of Diatomic Overlap 55 Austin Model 1 57 Parametric Method Number 3 58 Self-Consistent Field Convergers 58 Strong and Weak Points of NDDO Semiempirical Methods 61 MINDO/3 62 MNDO, AMI, and PM3 62 Theoretical Experiments 73 Stationary Points 74 General Procedure for Characterizing a Reaction 74 Reaction Path 75 Time-Dependent Phenomena 76 Future of Semiempirical Methods 77 Summary 78 References 78 3. Properties of Molecules by Direct Calculation 83 Clifford E. Dykstra, Joseph D. Augspurger, Bernard Kirtman, and David J. Malik Introduction 83 Overview of Quantum Mechanical Properties 84 Correspondence between Energy Derivatives and Properties 84 Differentiation of the Schrodinger Equation 85 The Development of Methods for Property Determinations 87 Semiempirical Approaches 87 Ab Initio Methods 89 Detailed View of Ab Initio Methods 92 Hamiltonians and Operators 92 Computational Organization of the Differentiation Process 95 Derivatives of Electronic Wavefunctions 97 Local Space Concepts for Extended Systems 99 Vibrations and Rotations 100 Direct Property Calculations 103 Electrical Properties 103 Magnetic Properties 107 Force Constants 109 Transition Probabilities and Optical Properties 110 Summary 111 References 112 4. The Application of Quantitative Design Strategies in Pesticide Discovery 119 Ernest L. Plummer Introduction 119 The Selection of a Strategy 122 The Well-Designed Substituent Set 126 The Ideal Substituent Set Should Cover All Factors That Control Activity 127 The Ideal Substituent Set Should Cover the Selected Factor Space as Completely as Possible 128 The Ideal Substituent Set Should Span Orthogonal Dimensions of Parameter Space 129 The Ideal Set Should Contain the Minimum Number of Substituents Necessary to Avoid Chance Correlations and Still Meet the Desired Goal 130 Target Compounds Should Be Chosen to Preserve Synthetic Resources But Should Not Be Chosen Just Because They Are Easy to Synthesize 131 The Derivatives Must Be Stable under the Conditions of Bioevaluation 131 Analysis Strategies 132 The Topliss Tree 132 Free-Wilson Analysis 135 A Strategy for Lead Optimization Using Multiple Linear Regression Analysis 138 Choose the Optimal Pattern for Substitution 139 Choose the Factors (Parameters) That Are Likely to Be Important 142 Select a Substituent Set 143 Synthesize and Submit for Biological Evaluation 152 Plot Each Parameter versus Activity 154 Generate Squared Terms if Justified by the Single Parameter Plots 157 Run All Combinations of the Chosen Parameters through Linear Regression Analysis to the Limits of Statistical Significance 158 Repeat the Process Until the QSAR Is Stable 160 Sequential Simplex Optimization (SSO) 161 Conclusion 164 References 165 5. Chemometrics and Multivariate Analysis in Analytical Chemistry 169 Peter C. Jurs Introduction 169 Response Surfaces, Sampling, and Optimization 170 Signal Processing 173 Principal Components Analysis and Factor Analysis 175 Calibration and Mixture Analysis 178 Classification and Clustering 182 Classification 183 Clustering 184 Library Searching 186 Molecular Structure-Property Relationships 188 Gas Chromatographic Retention Indices for Diverse Drug Compounds 192 Simulation of Carbon-13 Nuclear Magnetic Resonance Spectra of Methyl-Substituted Norbornan-2-ols 198 Summary and Conclusions 207 References 208 6. Searching Databases of Three-Dimensional Structures 213 Yvonne C. Martin, Mark G. Bures, and Peter Willet Why Are Such Methods Needed? 213 Tools for Searching Two-Dimensional Chemical Structures of Small Molecules 217 Computer Representation of Two-Dimensional Chemical Structures 218 Searching Files of Two-Dimensional Chemical Structures 220 Languages for Chemical Programming 222 System Design for Chemical Information Systems 224 Similarity of Small Molecules Based on Two-Dimensional Structure 225 Substituent Effects on Molecular Properties 225 Two-Dimensional Topological Descriptors of Molecular Shape 226 Similarity of Small Molecules Based on Three-Dimensional Structure 226 Three-Dimensional Similarity Based on Geometric Properties 227 Three-Dimensional Similarity Based on Steric Properties 231 Databases of Three-Dimensional Structures of Molecules 234 Searching Files of Three-Dimensional Structures of Small Molecules 236 Programs from the Cambridge Crystallographic Data Centre 236 Searching Based Principally on Shape Properties 237 Strategies Based on Screen Searching 238 Strategies Based on a Substructure Specification Language 243 Databases and Searching of Multiple Three-Dimensional Pharmacophoric Patterns 248 Searching Files of Three-Dimensional Protein Structures 249 The Protein Data Bank 249 Identification of Patterns of Atoms 249 Identification of Secondary Structure Motifs 252 Conclusions 253 Appendix: Sources of Databases and Programs 255 References 256 7. Molecular Surfaces 265 Paul G. Mezey Introduction 265 Molecular Body and Molecular Surface 266 Classical Models for Molecular Surfaces: Hard Spheres and van der Waals Surfaces (VDWSs) 267 Electron Density Contour Surfaces 269 The Density Domain Approach to Chemical Bonding (DDA) 271 Molecular Electrostatic Potential 274 Molecular Orbitals 276 Solvent Accessible Surfaces 278 Union Surfaces 279 Interpenetration of Molecular Contour Surfaces 281 Shape Analysis of Molecular Surfaces 282 Conclusions 288 References 289 8. Computer Simulation of Biomolecular Systems Using Molecular Dynamics and Free Energy Peturbation Methods 295 Terry P. Lybrand Introduction 295 Models 296 Methods 297 Energy Minimization 298 Normal Mode Analysis 298 Monte Carlo 299 Molecular Dynamics 300 Free Energy Pertubation Methods 308 Summary 314 References 315 9. Aspects of Molecular Modeling 321 Donald B. Boyd Introduction 321 Quantum Mechanics 323 Why Use Quantum Mechanics? 323 Theory 325 Approximations 326 Comparison of Ab Initio and Semiempirical MO Methods 328 Input 329 Output 331 Basis Sets for Ab Initio Calculations 332 Caveats on Basis Sets 334 Post-Hartree-Fock Treatments 334 Selection of an MO Method 336 Numerical Sensitivity of Geometry Optimization Procedures 337 Quality of Results from Quantum Mechanical Methods 339 Information from X-Ray Databases for Molecular Modeling 341 Standard Geometries 345 Distance Geometry 345 Summary 348 References 351 10. Successes of Computer-Assisted Molecular Design 355 Donald B. Boyd Levels of Success 355 Norfloxacin 359 Metamitron 360 Bromobutide 361 Myclobutanil 362 Conclusion 364 References 365 11. Perspectives on Ab Initio Calculations 373 Ernest R. Davidson Atomic Orbitals Do Not Work 375 The Error in 'P Is Largest Where 'P Is Largest 376 The Number of Electron Pairs Is N(N - l)/2 377 The Computer Cost, at Fixed Accuracy, Grows Like N! 378 Computers Do Not Solve Problems, People Do 379 Appendix: Compendium of Software for Molecular Modeling 383 Donald B. Boyd Personal Computers 384 Minicomputers-Superminicomputers-Workstations 387 Supercomputers 392 Subject Index 393