MOLECULAR ORBITAL THEORY
DENSITY FUNCTIONAL THEORY 1 ADVANCES IN DENSITY FUNCTIONAL BASED MODELING TECHNIQUES RECENT EXTENSIONS OF THE CAR PARRINELLO APPROACH 5 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 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 DFT WITHIN 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 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 3 APPLICATIONS OF CAR PARRINELLO MOLECULAR DYNAMICS IN BIOCHEMISTRY BINDING OF LIGANDS IN MYOGLOBIN 73 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 O2 BINDING 90 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 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 QM MM APPROACHES 5 AB INITIO METHODS IN THE STUDY OF REACTION MECHANISMS THEIR ROLE AND PERSPECTIVES IN MEDICINAL CHEMISTRY 157 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 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 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 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 8 1 INTRODUCTION 233 8 2 METHODOLOGY 235 8 3 AN EXAMPLE THAT FOCUSES ON VMIN THE CARCINOGENICITY OF HALOGENATED OLEFINS AND THEIR EPOXIDES 239