Carloni P., Alber F. (ed.) Methods and Principles in Medicinal Chemistry. Volume 17. Quantum Medicinal Chemistry

WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim, 2003. - 281 p.
Quantum-chemical methods have adapted an important role in medicinal chemistry. It is the intention of the present volume to document this role in adequate detail. Accordingly, the book is divided into three main sections.
The first section is dedicated to density functional theory. A description of advances in density functional based modelling techniques is followed by application examples in computational medicinal chemistry, biochemistry and drug design. The following section is focussed on QM/MM approaches and describes e.g. the use of ab initio methods in the study of reaction mechanisms.
The last section presents a survey of pharmaceutically relevant properties derived by quantum-chemical calculations such as molecular electrostatic potentials. In a finalizing chapter applications
of quantum-chemical methods to systems of biological and pharmacological relevance are described.

Contents

Preface

Foreword

List of Contributors
Outline of the Book

Density Functional Theory

Advances in Density-functional-based Modeling Techniques – Recent Extensions of the Car-Parrinello Approach
Daniel Sebastiani and Ursula Rцthlisberger

Introduction
The Car-Parrinello Approach – Basic Ideas
How It Can be Done
Ab Initio Molecular Dynamics Programs
Mixed Quantum Mechanical/Molecular Mechanical (QM/MM) Car-Parrinello Simulations
Gly-Ala Dipeptide in Aqueous Solution – Do We Need a Polarizable Force Field ?
Density-functional Perturbation Theory and the Calculation of Response Properties
Introduction to Density-functional Perturbation Theory
Basic Equations of Density-functional Perturbation Theory
NMR Chemical Shieldings within DFPT
Introduction to Nuclear Magnetic Resonance Chemical Shifts
NMR Chemical Shielding
Calculation of NMR Chemical Shifts in QM/MM Car-Parrinello Simulations
Introduction to Time-dependent Density-functional Theory (TD-DFT)
Basic Equations of TD-DFT
Applications of TD-DFT within the QM/MM Framework – Opsochromic Shift of Acetone in Water
Acknowledgments
References

Density-functional Theory Applications in Computational Medicinal Chemistry
Andrea Cavalli, Gerd Folkers, Maurizio Recanatini, and Leonardo Scapozza

Introduction
Density-functional Theory and Related Methods
Density-functional Theory
Ab Initio Molecular Dynamics
SAR Studies of Ligand-Target Interactions
The Case Study: Herpes Simplex Virus. Type 1 Thymidine Kinase Substrates and Inhibitors
Rationalizing Substrate Diversity – SAR of HSV1 TK Ligands
What Can be Leaed from this Case Study – From SAR to Drug Design
Theoretical Studies of Enzymatic Catalysis
The Phosphoryl Transfer Reaction
Cdc42-catalyzed GTP Hydrolysis
HIV-1 Integrase
Studies on Transition Metal Complexes
Radiopharmaceuticals
Conclusions and Perspectives
References

Applications of Car-Parrinello Molecular Dynamics in Biochemistry – Binding of Ligands in Myoglobin
Carme Rovira

Introduction
Computational Details
Myoglobin Active Center
Structure, Energy, and Electronic State
The Picket-fence-oxygen Biomimetic Complex
Interplay Structure/Electronic State
Optimized Structure and Energy of O₂ Binding
Heme-Ligand Dynamics
Interaction of the Heme with the Protein
Conclusions
Acknowledgments
References

Density-functional Theory in Drug Design – the Chemistry of the Anti-tumor Drug Cisplatin and Photoactive Psoralen Compounds
Johan Raber, Jorge Liano, and Leif A. Eriksson

Introduction
Density-functional Theory
Basic Equations
Gradient Corrections and Hybrid Functionals
Time-dependent Density-functional Response Theory (TD-DFRT)
Applicability and Applications
Modes of Action of Anti-tumor Drug Cisplatin
Activation Reactions
Interactions Between DNA and Cisplatin
Photochemistry of Psoralen Compounds
Ionization Potentials
Excitation Spectra
Acknowledgments
References

QM/MM Approaches

Ab Initio Methods in the Study of Reaction Mechanisms – Their Role and Perspectives in Medicinal Chemistry
Mikael Perakyla

Introduction
Methods
Hybrid QM/MM Potential
QM/MM Boundary – The Link Atom Approach
QM/MM Boundary – The Hybrid Orbital Approach
Thermodynamically Coupled QM/MM
Selected Applications of QM/MM Methods
Uracil-DNA Glycosylase
QM/MM Simulations of Quantum Effects
Miscellaneous Applications
Conclusions
References

Quantum-mechanical/Molecular-mechanical Methods in Medicinal Chemistry
Francesca Perruccio, Lars Ridder, and Adrian J. Mulholland

Introduction
Theory
Methodology
Basic Theory
QM/MM Partitioning Schemes
Practical Aspects of Modeling Enzyme Reactions
Choice and Preparation of the Starting Structure
Definition of the QM Region
Choice of the QM Method
Techniques for Reaction Modeling
Optimization of Transition Structures and Reaction Pathways
Dynamics and Free Energy Calculations
Some Recent Applications
Human Aldose Reductase
Glutathione S-Transferases
Influenza Neuraminidase
Human Thrombin
Human Immunodeficiency Virus Protease
Conclusions
References

Molecular Properties

Atoms in Medicinal Chemistry
Richard F.W. Bader, Cherif F. Matta, and Feando J. Martin

Why Define Atoms in Molecules?
Theory of Atoms in Molecules
Definition of Atoms and Molecular Structure
Definition of Atomic Properties
Atomic Charges, Multipole Moments and Volumes
QTAIM and Correlation of Physicochemical Properties
Use of Atomic Properties in QSAR
Use of Bond Critical Point Properties in QSAR
QTAIM and Molecular Similarity
Use of QTAIM in Theoretical Synthesis of Macromolecules
Assumed Perfect Transferability in the Synthesis of a Polypeptide
The Assembly of Buffered Open Systems in a Macrosynthesis
The Laplacian of the Density and the Lewis Model
The Laplacian and Acid-Base Reactivity
Molecular Complementarity
Conclusions
References

The Use of the Molecular Electrostatic Potential in Medicin Chemistry
Jane S. Murray and Peter Politzer

Introduction
Methodology
An Example that Focuses on Vmin – the Carcinogenicity of Halogenated Olefins and their Epoxides An Example Focusing on the General Pattes of Molecular Electrostatic Potentials – Toxicity of Dibenzo-p-dioxins and Analogs
Statistical Characterization of the Molecular Surface Electrostatic Potential – the General Interaction Properties Function (GIPF)
Summary
Acknowledgment
References

Applications of Quantum Chemical Methods in Drug Design
Hans-Dieter Holtje and Monika Holtje

Introduction
Application Examples
Force Field Parameters from Ab Initio Calculations
Equilibrium Geometry for a Dopamine-D3-Receptor Agonist
Searching for a Bioactive Conformation
Atomic Point Charges
Molecular Electrostatic Potentials
Molecular Orbital Calculations
Outlook
Acknowledgment
References

Subject Index