Reviews in Computational Chemistry

392 Subject Index

Encounter complexes, 88 Energy score, 33, 34, 43 Enrichment, 5, 40

Ensemble enriching multiple copy molecular dynamics, 90

Ensembles, 21

Enthalpy, 71

Enthalpy-entropy compensation, 65 Entropy, 24, 26, 81

Entropy terms, 27 Enzymes, 245

EPCISO (Effective and polarized spin-orbit CI), 170

EPDOCK, 15

Epitope, 64

Epstein-Nesbet perturbation theory, 169 Equilibrium, 244

Equilibrium constant, 238

Error rates in CAplus database, vi Essential dynamics, 83

Estrogen receptor, 39 Ethene, 135 Euclidean space, 18 Euler angles, 137

Euler rotation matrix, 140 Evolution, 14

Evolutionary programming, 14 Exchange integrals, 129 Excitations, 183

Excited state, 177, 241 Excited-state kinetics, 240 Excited-state lifetimes, 242 Exclusion principle, 108 Excretion, 38

Extended von Neumann neighborhood, 213

Factor Xa, 39, 41 False negatives, 4, 38

False positives, 3, 34, 38, 44, 77 Farnesyltransferase inhibitors, 39 Fast Fourier transforms, 76

Fermion irreducible representations, 140, 158

Filter functions, 34

Fine-structure splitting, 99, 134, 159, 170, 173, 193, 194

Finite basis, 162 First-order kinetics, 237

First-order perturbation theory, 126 First-order spin-orbit perturbation, 180 First-order spin-orbit splitting, 171 First-order transitions, 240

First-rank tensor operator, 144 Fitness function, 14, 15 Fitness score, 88

FK506-binding protein, 25, 32, 34, 39

FlexE, 21

Flexibase/FLOG docking algorithm, 11 Flexibases, 11

Flexibility, 83, 88 Flexibility penalty term, 29

Flexible docking, 10, 33, 39, 70, 74, 79, 80, 86, 88

Flexible ligands, x, 2, 11

FlexX, 2, 13, 19, 28, 32, 33, 35, 39, 40

FlexXc, 23

FLOG, 2, 27, 34, 39 Flowchart of docking, 35 Fluctuations, 208, 238, 244 Fluorescence, 183, 192, 241 Fold prediction, 62

Foldy-Wouthuysen transformation, 126 Force field, 19, 26, 28, 34, 207

Force field scoring, 26 Four-component ab initio method, 159 Fragmentation, 11

Fragment-based de novo ligand design, 23 Franck-Condon (FC) factors, 188

Free energies, 26

Free energy of binding, 28, 70, 83, 86 Free energy perturbation, 24, 70

Free movement probability, 215 Frozen-core approximation, 127 Frozen-core orbitals, 127

Frozen-core spin-orbit Hamiltonian, 129 FTDOCK, 77, 83, 85, 87

Full CI, 165 Fuzzy logic, vi

GAMBLER, 34

Gaussian basis functions, 162 Gaussian lobe functions, 161 General angular momenta, 114 Generalized Born/surface area, 27 Genetic algorithms (GA), 14, 88 Genetic docking algorithm, 40 Genomes, 62, 90, 260

Geometric features, 8

Geometric hashing, 7, 8, 12, 78, 79, 80 Global energy minima, 20, 25

Global optimum, 5 GOLD, 2, 15, 27, 35, 40

Gordon Research Conferences (GRCs), ix, 255

Gradient-based techniques, 74, 81

Subject Index

393

GRAMM, 77

Graph theory, 6, 261, 352

Gravity effect, 210, 216, 229

GREEN, 26

Grid, 16, 17, 26, 75

Ground state, 102

GROW, 13

Haloperidol, 39 Hamiltonian

Breit-Pauli spin-orbit, 125, 193 Dressed, 195

Effective one-electron spin-orbit, 132 Frozen-core spin-orbit, 129 Magnetic interaction, 146 Mean-field, 135

No-pair, 126, 167

Phenomenological spin-orbit, 147, 194 Spin-orbit, 124

Valence-only spin-orbit, 127 Zeroth-order regular approximation

(ZORA), 167

Hamiltonians, 100, 111, 124, 125, 127, 130, 132, 135, 143, 146, 151, 158, 159, 171, 175, 193

Hammerhead, 2, 14, 29 Haptic devices, 69 Hash table, 8, 12 Hashing, 7, 78, 79 Hashing function, 8 Hashing key, 8

Heat capacity, 224 Heavy atoms, 133, 174 Heavy elements, 100 Helicopter view, 17 Hemagglutinin, 38

Hermite Gaussian functions, 161 Hermitian, 111

Heuristic rules, 208, 248 Heuristic scoring schemes, 24 Hidden bias, 40

High throughput screening (HTS) methods, 4, 37

Hinge, 12

Hinge-bending motion, 67, 79

HINT, 25

HIV reverse transcriptase, 39 HIV-1 protease inhibitor, 39 Hole states, 172

Homology models, 2, 62, 90 Hot spot residue, 86

Hot spots, 63

Human growth hormone, 64

Human immunodeficiency virus (HIV-1) protease, 4, 8, 25, 30, 31, 38, 39

Hund’s case, 171, 174, 175 Hybrid methods, 19 Hydration, 82, 224 Hydration energy, 27 Hydrides, 171

Hydrogen bonding, 13, 15, 26, 27, 28, 64, 86

Hydrogen bond potentials, 27 Hydrophobic effect, 224 Hydrophobic interactions, 32, 65 Hydrophobic potentials, 27 Hylleras perturbation theory, 166

HyperChem, ix

Hyperfine splittings, 100, 146

ICM (Internal Coordinate Mechanics), 17, 18

Identity, 101, 141 Immiscible liquids, 229, 231 Implicit solvation model, 91

Incremental construction, 11, 13, 19, 22 Induced fit, 75, 82

Infinitesimal rotation, 109 Infinitesimal rotation operator, 112 Influenza virus, 41

Influenza virus neuraminidase, 2 Informatics, v, 259

Inhibitors, 62

Inosine monophosphate dehydrogenase, 4 Integrals, 131

Intensity borrowing, 182 Interaction center, 10 Interaction energy, 24 Interaction surface, 10 Interface surface patches, 62 Interfacial side chains, 79, 81

Interfacial surfaces in proteins, 62, 63, 83 Interleukin-4-alpha receptor, 64

Internal conversion (IC), 178, 241 Internal coordinate mechanics, 81 Internal coordinates, 17

Internet books, 259

Intersystem crossings (ISC), 100, 161, 178, 186, 193, 241

Intraligand interactions, 27, 32 Inverted state, 172

Ionic solvation effects, 235 Ionic strength, 65

Ion-pair interactions, 28 Irreducible representation, 136, 140 Irreducible tensor operators, 148

394 Subject Index

Jablonski diagram, 178 Jerusalem conferences, 260 jj coupling, 167

Joining parameters, 226

Joining trajectory parameter, 216

Journal of Chemical Information and Computer Science, xii

Journal of Computational Chemistry, xii Journal of Computer-Aided Molecular Design,

xii

Journal of Molecular Graphics and Modelling, xii

Journals, 258, 259

Kinetic behavior, 206 Kinetic reaction control, 240 Kirkwood equation, 81

Knowledge-based potentials, 30 Knowledge-based scoring functions, 24, 30 Kohn-Sham approximation, 167

Kramers degeneracy, 168 Kramers pairs, 167 Kronecker delta, 113

Laboratory automation books, 258 Ladder operators, 114

Laguerre polynomials, 78

Lande´ interval rule, 133, 172, 173, 174 Langevin dipoles, 81

Large-scale conformational changes, 67, 79, 83

Lead identification, 37, 43

Lead optimization, 2, 40, 41, 43 Lead structures, 5 Lennard-Jones function, 27, 72 Library design, 38

Lifetime calculations, 186 Lifetime of an excited state, 179 Ligand database, 36

Ligand design, 2, 40, 45 Ligand fragments, 41 Ligand solvation, 27

LIGIN, 19

LIGSITE, 36

Limited backtrack search, 14 Linear molecules, 156, 174 Linear momentum operator, 129 Linear representation, 14

Linear response approximation, 24 Lineweaver-Burk plots, 245 Lipophilic fragments, 231 Lipophilic interactions, 28 Lipophilicity, 29, 229, 245

Local minima, 17, 19 Local structural changes, 66

Long-range electrostatic interactions, 88 LS contracted spin-orbit configuration

interaction, 165 LUDI, 7, 9, 10, 23, 28

Luminescence quantum yields, 242 Lysozyme, 63

Lysozyme-HyHel5 antibody complex, 81

Macroscopic phenomena, 206 Magnetic dipole transition operator,

186

Magnetic dipole transitions, 182, 186 Magnetic dipoles, 102, 186 Magnetic field, 101, 103, 108

Magnetic interaction Hamiltonians, 146 Magnetic interactions, 99, 100 Magnetic quantum numbers, 107 Magnetic resonance, 159

Malaria protease, 38 Manual docking, 41 Markov chain, 19 Markov processes, 206

Mass spectrometry (MS), 62 Mass-velocity corrections, 159 Materials books, 319

Matrix elements, 148

Matrix elements of angular momentum operators, 119

Matrix metalloproteinase stromelysin (MMP-3), 33

MCM method, 18 MCSS technique, 23 MDL databases, 36

Mean-field approximation, 185 Mean-field Hamiltonian, 135 Mean-field potentials, 33 Mean-field scoring function, 31 Mean-field spin-orbit operators, 162 Melting process, 226

Membrane, 231, 232 Membrane permeability, 232 Metabolism, 38

Metallo-beta-lactamase inhibitors, 39 Methylene, 155, 156

Metropolis criterion, 16, 81 Micelle formation, 231 Michaelis-Menten model, 245 Microcalorimetry, 23

MIMUMBA (torsional angle database), 36 Misspellings in CAplus, vii Mitogen-activated protein (MAP) kinase, 4

Subject Index

395

Molecular affinity potentials, 16 Molecular design books, 261, 345 Molecular docking, 4, 7

Molecular dynamics, 4, 16, 70, 82, 207 Molecular fragments, 4, 6

Molecular mechanics, 71, 75, 260 Molecular modeling books, 331 Molecular recognition, 1, 16 Molecular simulation, 16, 260, 335 Molecular Simulations, Inc., viii Molecular structures, 208 Momentum operator, 194

Monte Carlo (MC) algorithms, 17, 19 Monte Carlo simulations, 206, 207 Monte Carlo trajectories, 82

Moore neighborhood, 213 Movement probability, 215 Movement rules, 213, 215 Moving cell, 210

Multiconfiguration self-consistent field (MCSCF), 166, 169

MULTIDOCK, 79 Multiple copy MD, 89 Multipole expansion, 186 Multireference CI, 183

Multireference CI wave functions, 185 Multireference singles and doubles CI

(MRSDCI), 169

Natural orbitals (NOs), 169 Neighborhoods, 212, 213 Neural networks books, 260 Neuraminidase, 32, 34, 41 Neuraminidase inhibitors, 42 Newtonian mechanics, 16 Nickel atom, 173, 174 Nitric oxide, 179

No-pair Hamiltonian, 167 No-pair operators, 162

No-pair spin-orbit Hamiltonian, 126 Non-rotameric states, 81 Nonbonded cutoff schemes, 28 Nonlinear molecules, 154

Nonoccluded atom pair interactions, 29 Nonradiative depletion mechanisms, 183, 186 Nonradiative processes, 241

Nonradiative transitions, 100, 161, 177, 187, 192, 193

Normal mode analysis, 83 Normal Zeeman effect, 103

Nuclear magnetic resonance (NMR), 1, 39, 62, 100

Nuclear Zeeman effect, 107

Obituaries, vii One-electron integral, 128 Onset of percolation, 236

Open-shell electronic states, 133 Operators

Angular momentum, 111, 112, 144, 151, 157 Antisymmetric, 111

Breit-Pauli spin-spin coupling, 147 Compound tensor, 145

Dipolar spin-spin coupling, 147, 147 Dirac-Coulomb-Breit, 124 Empirical one-electron, 132 First-rank tensor, 144

Infinitesimal rotation, 112 Irreducible tensor, 148 Ladder, 114

Linear momentum, 129 Magnetic dipole transition, 186

Matrix elements of angular momentum, 119 Mean-field spin-orbit, 162

Momentum, 194 No-pair, 162 Phenomenological, 152

Phenomenological electronic spin-spin, 176 Projection, 101

Pseudo-potential spin-orbit, 133 Relativistic kinetic energy, 127 Scalar, 144

Second-rank tensor, 144 Shift, 114, 171

Spin, 122 Spin-orbit, 125, 147

Spin-orbit coupling, 133 Spin-orbit mean-field, 134 Step, 144

Step-down, 114 Step-up, 114 Step/shift/ladder, 114 Symmetry, 143

Tensor, 137, 143, 145, 146, 171 Vector, 144

Wood-Boring spin-orbit, 134 Optimal rigid-body orientation, 75 Optimization, 16, 88

Orbital angular momentum, 109, 112 Oscillator strengths, 182

Osmotic effect, 233

Oxygen, 100, 179, 187, 190, 192, 242

Parallel Virtual Machine (PVM), 37 Partial protein flexibility, 21 Particle concept, 14

Particle states, 172

396 Subject Index

Partitioning, 229 Paschen-Back effect, 106, 108 Passive diffusion, 232 Pattern recognition, 9

Pauli principle, 99, 108 Pauli spin matrices, 123 Percolation, 235 Percolation threshold, 236

Perturbation theory, 181, 186 Perturbational approaches, 163 pH, 65

Pharmacophore, 26 Phase changes, 205

Phenomenological electronic spin-spin operator, 176

Phenomenological operators, 152 Phenomenological spin-orbit Hamiltonian,

147, 194 Phospholipase A2, 2

Phosphorescence, 100, 179, 183, 193, 241

Phosphorescence lifetimes, 186 Physical chemistry books, 260 Physical properties, 205 Pi-stacking interactions, 28

Piecewise linear potential (PLP), 25, 34 Place & join, 11

Placement lists, 12 Planck’s constant, 102 Plastocyanin, 82

PLP scoring function, 25 PMF-score, 33, 34, 43 Poisson equation, 19

Poisson-Boltzmann electrostatic forces, 75, 81, 82

Poisson-Boltzmann equation, 18, 72, 77 Polymer books, 319

Pose clustering, 9, 13 Positronic states, 126 Postprocessing, 37 Potential energies, 26, 101 Potential energy curves, 188

Potentials of mean force (PMF), 30 Predissociation, 187, 190, 191, 194 Preequilibrium, 240

PRO_LEADS, 19, 29 PRO_SELECT, 22

Probabilistic cellular automata, 214 Probabilistic microscopic events, 206 Probabilistic movement rules, 213 Probabilistic rules, 209

Probability amplitudes, 101 Proceedings of conferences, 322

PRODOCK, 18 Profit, 45

Projection operators, 101 Proprietary databases, 37 Proteases, 62

Protein complexes, 69

Protein Data Bank (PDB), 1, 31, 32, 73 Protein engineering, 63

Protein flexibility, 5, 20, 21, 44, 79 Protein folding, 30

Protein structure evaluation, 30 Protein structures, 2, 26 Protein surfaces, 62

Protein targets, 1

Protein binding pocket, 24 Protein-ligand binding, 20, 28, 29 Protein-ligand binding affinities, 31

Protein-ligand complex, 1, 2, 19, 24, 28, 30, 40, 44, 45

Protein-ligand conformations, 27, 34 Protein-ligand docking, 5, 16 Protein-ligand interactions, 25, 30, 36 Protein-ligand interface, 14 Protein-ligand scoring functions, 30 Protein-protein binding, 65 Protein-protein docking, 61 Protein-protein interactions, 28 Protein-protein interfaces, 62, 67, 70, 87 Proteins, 30

Proteomics, x, 90 Protonation states, 36

Pseudo-first-order reaction, 245 Pseudo-potential spin-orbit operators,

133

Publication rates, 353

Quadratic shape descriptors (QSD), 26 Quantitative structure-activity relationships

(QSAR), 260, 261, 345 Quantum chemistry, 99, 293, 304 Quantum effect, 108

Quantum field theory, 107 Quantum mechanics, xii, 101, 260

Quantum numbers, 108, 148, 150, 193 Quantum theory, 293

Quantum Theory Project (QTP), ix Quasi-degenerate perturbation theory, 133,

165, 168, 186

QXP, 17

Radial amplitudes, 160

Radiation field, 186

Subject Index

397

Radiative depletion, 187 Radiative lifetimes, 185, 187 Radiative processes, 240 Radiative transitions, 179, 193 Radioactive decay, 237 Random search, 19

Rate constants, 63, 75, 206 Rate-limiting-step, 240 Rational drug design, 45, 62

Rayleigh-Schro¨ dinger perturbation theory, 163, 179

Reaction-diffusion systems, 242 Receptor critical points, 78

Receptor site, 5, 11, 13, 17, 19, 36, 41 Reduced matrix element, 151 Reference frame, 8

REGISTRY database, v

Regular state, 172

Regulating membrane passage, 233 Relative gravity parameter, 219 Relativistic CI (RCI), 169 Relativistic corrections, 159 Relativistic effect, xi, 99, 194

Relativistic effective core potentials (RECP), 133, 159

Relativistic effective pseudo-potentials, 134 Relativistic field theory, 124

Relativistic kinetic energy operator, 127 Relativistic quantum theory, 101 Reorganization energy, 24

R-group selection, 23 Response theory, 166, 179 Retardation term, 125

Reversible second-order reaction, 244

Reviews in Computational Chemistry, vi, xii, 255

Rigid-body docking, 6, 11, 19, 26, 39, 69, 73, 74, 81, 83

RNase H, 38 Rotamer library, 81

Rotatable bonds, 11, 28 Rotation matrices, 138 Rotational angle space, 77 Rotational predissociation, 192 Rovibronic coupling, 161

Rovibronic spectra, 170, 171, 187 Rule-based format translation, 36 Russell-Saunders (LS) coupling, 155, 156 Russell-Saunders states, 182

Rys quadrature techniques, 161

Salt bridges, 26, 86

Sampling, 3, 70

Sampling properties, 19

SANDOCK, 26

Sanibel Symposia, ix, 260 SAR by NMR, 41

Scalar operator, 144

Schro¨ dinger equation, 113, 187, 188 Schumann-Runge bands, 190

SciFinder, v, vi, 256 SCORE, 34

Scoring, 1, 23, 33, 70, 71, 77

Scoring functions, x, 3, 15, 19, 24, 44, 69, 75 Screening methods, 1

Second-order kinetics, 242 Second-order rate law, 243 Second-order spin-orbit splitting, 175 Second-rank tensor operator, 144 Selection rules, 137, 146, 158 Self-quenching rates, 177 Self-reproducing automata, 208

Semiempirical molecular orbital method, viii Shannon information content, 237

Shape complementary scores, 24, 25, 26 Shift operators, 114, 171

Sialic acid, 42

Side-chain conformations, 20, 36, 66, 67, 73, 81, 86, 87

Side-chain flexibility, 86 Side-chain optimization, 81, 86 Side-chain torsion dynamics, 88 Silver atoms, 101

Simian immunodeficiency virus (SIV), 30 Simulated annealing, 16, 75

Single excitations, 128, 129, 130 Size extensive, 165

Skew symmetric matrix, 168 Slater-Condon rules, 129, 163 Slater determinants, 128 Slater-type orbitals (STOs), 161 Small fragments, 41

SMoG, 31

Soft van der Waals potentials, 27, 28 Solubility, 224

Solute dissolution, 226 Solution phenomena, 210 Solvated interfacial region, 86 Solvation, 18, 91

Solvation energies, 24, 25, 27 Solvation free energy, 28, 81 Solvent effects, 183

Solvent-accessible surface (SAS), 18, 20, 26, 32, 65, 71, 82

SPDIAG, 169 SPECITOPE, 21, 26

398 Subject Index

Spectroscopy books, 289 Spherical harmonics, 78, 112 Spin, 99, 101, 108, 121, 159

Spin angular momentum, 108, 121 Spin-coupling coefficients, 150

Spin density functional methods, 167 Spin flip, 186

Spin-forbidden electric dipole transition, 194 Spin-forbidden radiative transitions, 179,

182

Spin-forbidden transitions, 100, 177, 186 Spin-free frozen-core approximation, 127 Spin-free state shifted (SFSS) SOCI method,

169

Spin magnetic moment, 108 Spin multiplet, 99

Spin operators, 122 Spin orbitals, 128

Spin-orbit CI, 168, 179, 194

Spin-orbit coupling, xi, 99, 146, 152, 156, 159, 163, 167, 168, 177, 193

Spin-orbit coupling operators, 133 Spin-orbit Hamiltonians, 124 Spin-orbit integrals, 161 Spin-orbit mean-field operator, 134 Spin-orbit operators, 125, 147

Spin-orbit perturbed wave functions, 179 Spin-orbit splitting, 157, 194

Spinors, 122, 136

Spinor transformations, 139 Spin-polarization, 160

Spin-spin coupling, 100, 124, 147, 156 Spin-spin interaction, 194 Spin-vibronic interactions, 185 Spreadsheets, 259

Statistical mechanics books, 261 Steady-state approximation, 240 Step operators, 144

Step-down operators, 114 Step-up operators, 114 Step/shift/ladder operators, 114

Stern-Gerlach experiment, 100, 101, 102 Stern-Volmer plot, 177

STN system, v Stochastic dynamics, 75

Stochastic master equation, 206 Strain energy, 26, 34 Streptavidin, 30, 39 Stromelysin, 32

Structurally diverse compounds, 3 Structure-activity relationships (SAR), 2 Structure-based ligand design, 40

Sum-over-states methods, 166, 194 Supermultiplet approach, 170 Surface charges, 28

Surface complementarity, 25, 29, 31, 34 Surface features, 78

Surface descriptors, 25

Surface matching algorithm, 17 Surface plasmon resonance, 23 Surface-related properties, 29

SYBYL, 34 Symmetry, 136, 165

Symmetry operators, 143 Synchronous movement, 213 Synthesis, 3

Tabu list, 19 Tabu search, 19 Taylor series, 138

Template molecule, 22

Tensor operators, 137, 143, 145, 146, 171 Tensor properties, 146

Thallium atom, 160

Theoretical Chemistry Accounts, xii

Thermodynamic reaction control, 240 Thermochemistry books, 289 Thiocarbonyls, 183

Thrombin, 39

Thrombin inhibitors, 23, 33 Thymidylate synthase, 38 Time-dependent perturbation theory, 187 Time-dependent populations, 206 Torsion dynamics, 86

Torus, 210

Toxicity, 38

Transition functions, 213, 215 Transition moment, 181, 182 Transition probabilities, 159, 178, 182 Transition rate, 208

Transition rules, 215 Tree structure, 22 True hit, 38

True positives, 38

Truncated CI expansion, 165 Trypanothione reductase, 39 Two-electron integrals, 135

UHBD, 77

Valence electron, 107

Valence-only spin-orbit Hamiltonian, 127

VALIDATE, 29

van der Waals interactions, 72

Subject Index

399

van der Waals potential, 18, 26, 27, 28 Vapor pressure, 224

Variational collapse, 167

Variational perturbation theory, 166, 179, 194 Variational procedures, 166

Variegated cell, 211, 231 Vector operator, 144 Vibrational averaging, 174 Vibrational continuum, 187

Vibrational coordinate, 170, 188, 191 Vibrational wave functions, 188, 190, 194 Vibrationally bound states, 188 Vibrationally unbound states, 194

Viral replication cycle, 42 Virtual compounds, 3, 38 Virtual photons, 124 Virtual reality, 69 Virtual SAR by NMR, 4

Virtual screening, 3, 4, 13, 21, 35, 37, 43, 44

Viscosity, 224 Visualization books, 259 Volume overlap, 25

von Neumann neighborhood, 213, 222

Water, 9, 14, 32, 63, 65, 81, 86, 91, 210, 213, 221, 224

Water clusters, 224

Water-mediated hydrogen-bonding, 86 Water properties, 226

Water structure, 235 Wave functions

Continuum, 189 Multireference CI, 185 Spin-orbit perturbed, 179 Vibrational, 188, 190, 194

Weakly active chemical entities, 34 Wentzel-Rice formula, 189

WHAT IF, 64

Wigner-Eckart theorem, 137, 148, 156, 158, 193

Wood-Boring spin-orbit operators, 134 Workstation clusters, 37

World Drug Index, 39

X-PLOT, 64

X-ray crystallography, 1, 62

Zeeman effect, 103, 105 Zeeman spectroscopy, 100 Zero-field splitting, 99, 193

Zeroth-order regular approximation Hamiltonian (ZORA), 167

ZINDO, viii

Reviews in Computational Chemistry, Volume 17. Edited by Kenny B. Lipkowitz, Donald B. Boyd Copyright 2001 John Wiley & Sons, Inc.

ISBNs: 0-471-39845-4 (Hardcover); 0-471-22441-3 (Electronic)

CHAPTER 1

Small Molecule Docking and Scoring

Ingo Muegge* and Matthias Rareyy

*Bayer Research Center, 400 Morgan Lane, West Haven, Connecticut 06516, and yGerman National Research Center for Information Technology (GMD), Institute for Algorithms

and Scientific Computing (SCAI), Schloss Birlinghoven, D-53754 Sankt Augustin, Germany

INTRODUCTION

Molecular recognition is a central phenomenon in biochemistry. The highly specific recognition of, for example, enzymes and their substrates, protein receptors and their signal inducing ligands, or antigens and their antibodies in biological systems, is crucial to make complex life forms work. A detailed understanding of molecular recognition mechanisms is of particular interest in drug discovery, because most drugs interact with protein targets such as enzymes or receptors. To understand in detail the energetics of a protein interacting with a ligand that may be a potential drug candidate, one has to know the structure of the protein–ligand complex at atomic resolution. Protein–ligand structures are usually solved by X-ray crystallography1–4 or by nuclear magnetic resonance (NMR) spectroscopy.5–8 The Protein Data Bank

(PDB) presently contains about 15,000 protein structures9,10 and grows at a pace of about seven additional structures per day.11,12 For a particular protein

structure that is crystallized for a drug discovery program, fast screening methods have been developed that can process up to several thousand compounds soaked into the crystal.13 NMR screening methods have also been employed

1

2 Small Molecule Docking and Scoring

that connect structural measurements (chemical shifts of amino acid residues in the binding site) to binding affinity evaluation.14 However, these methods have obvious limitations; they depend on protein samples and crystals. Also, only a limited number of small molecules can be analyzed by physical chemistry experiments due to cost and time constraints.

The rapid advancement in X-ray crystallography and NMR spectroscopy provides a large number of solved protein structures. However, computational approaches are promising alternatives to crystallographic and NMR screening techniques. Computational methods that predict the three-dimensional (3D) structure of a protein–ligand complex are sometimes referred to as molecular docking approaches.15 Protein structures can be employed to dock ligands into the binding site of the protein and to study the intermolecular interactions. The prediction of ligand-binding modes can help in guiding, for instance, medicinal chemists exploring structure-activity relationships (SAR) in the lead optimization phase of a drug discovery effort. (A lead is a compound that shows biological activity and has the potential of being structurally modified for improved bioactivity.) Docking is applied here as a tool for ligand design complementing other structure-based methods such as de novo design.16 In the absence of experimental structures, homology models17,18 or pseudo-receptor models19 are sometimes used. Note, however, that the quality of a protein structure—whether experimental or computational—is crucial, because small changes in protein structure can influence the outcome of docking experiments dramatically.20 Ideally, the atomic resolution of crystal structures should

˚ 21

be below 2.5 A.

A challenge for molecular docking as a ligand design tool lies in the identification of the correct binding geometry of the ligand in the binding site (binding mode). In some cases, finding the correct binding mode is complicated by the observation that similar ligands unexpectedly bind in quite different orientations in the receptor site. Examples include the inhibitor MJ33 in phospholipase A222 and BANA113 in influenza virus neuraminidase23 discussed in the section on Applications. To find the correct binding mode of a ligand in the receptor site, an adequate sampling of conformational space available to a flexible ligand molecule in the protein binding pocket is required. The high flexibility of a typical ligand requires effective sampling methods. It also somewhat separates protein–ligand docking from the related protein–protein docking problem to be reviewed by Ehrlich and Wade24 in this book. In contrast to a globular protein, a small molecule is often not constrained in its overall shape. Also, shape alone is not a sufficient descriptor to identify low-energy conformations of a protein–ligand complex.25

Several docking algorithms (e.g., DOCK,26–28 FlexX,29–31 Hammerhead,32 GOLD,21 AutoDOCK,33 FLOG34) have been developed that place rigid or flexible ligands in mostly rigid—but recently also flexible—protein binding sites. All these methods/programs consist of two more or less intertwined parts: the sampling of the configuration space and the scoring of protein–ligand