Quantum Medicinal Chemistry

292 Pages·2003·2.774 MB·English

by  Paolo Carloni, Frank Alber, Raimund Mannhold, Hugo Kubinyi, Gerd Folkers

Quantum Medicinal Chemistry
Edited by
Paolo Carloni and Frank Alber
QuantumMedicinalChemistry.EditedbyP.Carloni,F.Alber
Copyright©2003WILEY-VCHVerlagGmbH&Co.KGaA,Weinheim
ISBN:3-527-30456-8
Methods and Principles in Medicinal Chemistry
Edited by
R. Mannhold, H. Kubinyi, G. Folkers
Editorial Board
H.-D. Höltje, H. Timmerman,
J. Vacca, H. van de Waterbeemd, T. Wieland
Quantum Medicinal Chemistry
Edited by
Paolo Carloni and Frank Alber
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V
Contents
Preface XI
Foreword XIII
List of Contributors XV
Outline of the Book 1
Density Functional Theory
1 Advances in Density-functional-based Modeling
Techniques – Recent Extensions of the Car-Parrinello
Approach 5
Daniel Sebastiani and Ursula Röthlisberger
1.1 Introduction 5
1.2 The Car-Parrinello Approach – Basic Ideas 6
1.2.1 How It Can be Done 8
1.2.2 Ab Initio Molecular Dynamics Programs 15
1.3 Mixed Quantum Mechanical/Molecular
Mechanical (QM/MM) Car-Parrinello Simulations 15
1.3.1 Gly-Ala Dipeptide in Aqueous Solution –
Do We Need a Polarizable Force Field? 19
1.4 Density-functional Perturbation Theory
and the Calculation of Response Properties 21
1.4.1 Introduction to Density-functional
Perturbation Theory 21
1.4.2 Basic Equations of Density-functional
Perturbation Theory 22
1.4.3 NMR Chemical Shieldings within DFPT 26
QuantumMedicinalChemistry.EditedbyP.Carloni,F.Alber
Copyright©2003WILEY-VCHVerlagGmbH&Co.KGaA,Weinheim
ISBN:3-527-30456-8
VI Contents
1.4.3.1 Introduction to Nuclear Magnetic Resonance
Chemical Shifts 26
1.4.3.2 NMR Chemical Shielding 27
1.4.3.3 Calculation of NMR Chemical Shifts in QM/MM
Car-Parrinello Simulations 30
1.5 Introduction to Time-dependent Density-functional
Theory (TD-DFT) 32
1.5.1 Basic Equations of TD-DFT 33
1.5.2 Applications of TD-DFTwithin the QM/MM
Framework – Opsochromic Shift of Acetone
in Water 35
1.6 Acknowledgments 36
1.7 References 36
2 Density-functional Theory Applications
in Computational Medicinal Chemistry 41
Andrea Cavalli, Gerd Folkers, Maurizio Recanatini,
and Leonardo Scapozza
2.1 Introduction 41
2.2 Density-functional Theory and Related Methods 42
2.2.1 Density-functional Theory 42
2.2.2 Ab Initio Molecular Dynamics 45
2.3 SAR Studies of Ligand-Target Interactions 48
2.3.1 The Case Study: Herpes Simplex Virus Type 1
Thymidine Kinase Substrates and Inhibitors 48
2.3.1.1 Rationalizing Substrate Diversity –
SAR of HSV1 TK Ligands 51
2.3.1.2 What Can be Learned from this Case Study –
From SAR to Drug Design 56
2.4 Theoretical Studies of Enzymatic Catalysis 57
2.4.1 The Phosphoryl Transfer Reaction 58
2.4.1.1 Cdc42-catalyzed GTP Hydrolysis 58
2.4.1.2 HIV-1 Integrase 63
2.5 Studies on Transition Metal Complexes 64
2.5.1 Radiopharmaceuticals 65
2.6 Conclusions and Perspectives 67
2.7 References 68
Contents VII
3 Applications of Car-Parrinello Molecular Dynamics
in Biochemistry – Binding of Ligands in Myoglobin 73
Carme Rovira
3.1 Introduction 74
3.2 Computational Details 79
3.3 Myoglobin Active Center 81
3.3.1 Structure, Energy, and Electronic State 81
3.3.2 The Picket-fence-oxygen Biomimetic Complex 86
3.3.2.1 Interplay Structure/Electronic State 86
3.3.2.2 Optimized Structure and Energy of O Binding 90
2
3.3.3 Heme-Ligand Dynamics 93
3.4 Interaction of the Heme with the Protein 99
3.5 Conclusions 106
3.6 Acknowledgments 108
3.7 References 108
4 Density-functional Theory in Drug Design –
the Chemistry of the Anti-tumor Drug Cisplatin
and Photoactive Psoralen Compounds 113
Johan Raber, Jorge Liano, and Leif A. Eriksson
4.1 Introduction 113
4.2 Density-functional Theory 114
4.2.1 Basic Equations 115
4.2.2 Gradient Corrections and Hybrid Functionals 117
4.2.3 Time-dependent Density-functional Response
Theory (TD-DFRT) 120
4.2.4 Applicability and Applications 122
4.3 Modes of Action of Anti-tumor Drug Cisplatin 124
4.3.1 Activation Reactions 127
4.3.2 Interactions Between DNA and Cisplatin 134
4.4 Photochemistry of Psoralen Compounds 141
4.4.1 Ionization Potentials 143
4.4.2 Excitation Spectra 146
4.5 Acknowledgments 150
4.6 References 150
VIII Contents
QM/MM Approaches
5 Ab Initio Methods in the Study of Reaction
Mechanisms – Their Role and Perspectives
in Medicinal Chemistry 157
Mikael Peräkylä
5.1 Introduction 157
5.2 Methods 161
5.2.1 Hybrid QM/MM Potential 161
5.2.2 QM/MM Boundary – The Link Atom Approach 161
5.2.3 QM/MM Boundary – The Hybrid
Orbital Approach 165
5.3 Thermodynamically Coupled QM/MM 166
5.4 Selected Applications of QM/MM Methods 168
5.4.1 Uracil-DNA Glycosylase 168
5.4.2 QM/MM Simulations of Quantum Effects 169
5.4.3 Miscellaneous Applications 170
5.5 Conclusions 173
5.6 References 173
6 Quantum-mechanical/Molecular-mechanical
Methods in Medicinal Chemistry 177
Francesca Perruccio, Lars Ridder,
and Adrian J. Mulholland
6.1 Introduction 177
6.2 Theory 178
6.2.1 Methodology 178
6.2.2 Basic Theory 179
6.2.3 QM/MM Partitioning Schemes 180
6.3 Practical Aspects of Modeling Enzyme Reactions 182
6.3.1 Choice and Preparation of the Starting Structure 182
6.3.2 Definition of the QM Region 183
6.3.3 Choice of the QM Method 184
6.4 Techniques for Reaction Modeling 185
6.4.1 Optimization of Transition Structures
and Reaction Pathways 185
6.4.2 Dynamics and Free Energy Calculations 186
6.5 Some Recent Applications 189
6.5.1 Human Aldose Reductase 189
6.5.2 Glutathione S-Transferases 191
6.5.3 Influenza Neuraminidase 193
Contents IX
6.5.4 Human Thrombin 193
6.5.5 Human Immunodeficiency Virus Protease 194
6.6 Conclusions 195
6.7 References 195
Molecular Properties
7 Atoms in Medicinal Chemistry 201
Richard F.W. Bader, Cherif F. Matta,
and Fernando J. Martin
7.1 Why Define Atoms in Molecules? 201
7.2 Theory of Atoms in Molecules 202
7.2.1 Definition of Atoms and Molecular Structure 203
7.3 Definition of Atomic Properties 208
7.3.1 Atomic Charges, Multipole Moments and Volumes 209
7.4 QTAIM and Correlation of Physicochemical
Properties 211
7.4.1 Use of Atomic Properties in QSAR 211
7.4.2 Use of Bond Critical Point Properties in QSAR 213
7.4.3 QTAIM and Molecular Similarity 215
7.5 Use of QTAIM in Theoretical Synthesis
of Macromolecules 218
7.5.1 Assumed Perfect Transferability in the Synthesis
of a Polypeptide 219
7.5.2 The Assembly of Buffered Open Systems
in a Macrosynthesis 222
7.6 The Laplacian of the Density and the Lewis Model 224
7.6.1 The Laplacian and Acid-Base Reactivity 225
7.6.2 Molecular Complementarity 228
7.7 Conclusions 229
7.8 References 230
8 The Use of the Molecular Electrostatic Potential
in Medicin Chemistry 233
Jane S. Murray and Peter Politzer
8.1 Introduction 233
8.2 Methodology 235
8.3 An Example that Focuses on V –
min
the Carcinogenicity of Halogenated Olefins
and their Epoxides 239