مرزهای شیمی محاسباتی / جلد ۳

In Chapter 4 "Elucidating Allosteric Communications in Proteins Via Computational Methods", the authors present a review of the application of different normal mode analyses based on molecular dynamics methods to understanding allosteric communication in proteins. Alakent and Ince also present the application of graph theory, perturbation methods, and i statistical methods to investigate allosteric mechanisms. The authors of Chapter 5 "Information-theoretic chemical space for many electron systems: from atoms to biological and pharmacological molecules" review the utility of an information-theoretic three-dimensional (IT-3D) space to unveil the unique physical, chemical and biological aspects of a great diversity of many electron systems. These multiple electrons systems range from simple atomic systems to more complex systems such as amino acids. Esquivel et al. claim that "All chemical families recognized by the existing energybased classifications are embraced by this entropic scheme". CONTENTS 6 PREFACE 10 List of Contributors 12 In Silico Approaches for Drug Discovery and Development 14 1. INTRODUCTION 14 2. COMPUTER AIDED DRUG DESIGN STRATEGIES 16 2.1. Ligand Based Drug Discovery 17 2.2. Structure Based Drug Discovery 19 3. TOPICS IN CADD 20 3.1. Databases 21 3.1.1. Small Molecule Databases 21 3.1.2. Preparation of Ligand Libraries 21 3.1.3. Virtual Combinatorial libraries 23 3.1.4. Representation of Small Molecules 23 3.1.5. Molecular Descriptors/Features 24 3.2. Target Databases for Computer-Aided Drug Design 24 3.3. Similarity Searches 25 3.4. Quantitative Structure-Activity Relationship (QSAR) 27 3.4.1. Classical QSAR (1D/2D) 28 3.4.2. 3D-QSAR 29 3.4.3. Multidimensional QSAR 30 3.5. Pharmacophores 31 3.6. Comparative Modeling 33 3.7. Binding Site Detection and Characterization 33 3.8. Protein – Ligand Docking 34 3.8.1. Molecular Docking Methods 38 3.8.2. Protein Flexibility in Docking 42 4. MOLECULAR DYNAMICS SIMULATIONS IN DRUG DISCOVERY AND DESIGN 43 4.1. MD Simulations 44 4.2. Refinement of Homology Models 45 4.3. Combining Docking and MD Simulations 46 4.3.1. Receptor Conformation (Preparation of Receptor Structure) 46 4.3.2. Ensemble Generation 47 4.3.3. Refinement of Docked Complexes 48 4.4. Free Energy Calculations 49 5. ASSESSMENT OF ABSORPTION DISTRIBUTION METABOLISM EXCRETION AND TOXICITY PROPERTIES 51 5.1. Drug Attrition in the Drug Development Phase 52 5.2. Compound Library Filters 52 5.3. Drug Metabolism: Cytochrome P450 54 5.4. Prediction of Human Ether-A-Go-Go Related Gene Binding 56 6. PROTEIN – PROTEIN INTERACTIONS AS DRUG TRAGETS 57 6.1. Peptide and Peptidomimetics as ppi Inhibitors 58 CONFLICT OF INTEREST 60 ACKNOWLEDGEMENTS 61 REFERENCES 61 Computational Chemistry Assisted Design and Screening of Ligand-Solvent Systems for Metal Ion Separation 86 1. INTRODUCTION 87 2. COMPUTATIONAL METHODOLOGY 88 2.1. Moller-Plesset Perturbation Theory 89 2.2. Couple Cluster Method 90 2.3. Density Functional Theory (DFT) 92 2.4. Local Density Approximation 93 2.5. Generalized Gradient Approximation 94 2.6. Conductor Like Screening Model (COSMO) 95 2.7. Basis Set Superposition Error (BSSE) 96 2.8. Present Approach of Design and Evaluation 96 2.8.1. Evaluation of Structural Parameters 97 2.8.2. Evaluation of Interaction Parameters 97 2.8.3. Evaluation of Thermodynamic Parameters 98 2.8.4. Calculation of Separation Parameters 99 3. STRUCTURES AND STRCTURAL PARAMETERS 100 3.1. Microsolvation of Metal Ions 100 3.2. Coordination Number and Radial Distribution Function 102 3.3. Macrocyclic Crown Ethers 105 3.4. Cavity Size of the Host Crown Ethers 106 3.5. Tuned Extended Crown Ethers 112 3.6. Conformation 112 3.7. Donors 114 3.8. Calix-Crown Ethers 117 3.9. Organophosphorus Ligands 122 3.10. Diglycolamide Ligands 123 3.11. Carbon Nanotube Functionalized Diglycolamic Acids 127 3.12. Ionic Liquids 129 4. INTERACTION PARAMETERS -BINDING ENEGY 132 4.1. Cavity Dependence 134 4.2. Conformer Dependence 137 4.3. Donor Atom Dependence 138 4.4. Binding Interaction towards Calix-Crown Ethers 139 4.5. Binding Interaction with Organophosphorous Ligands 141 4.6. Binding Interaction with Diglycolamide Ligands 142 4.7. Binding Interaction with CNT-DGA 143 5. THEMODYNAMIC PARAMETERS - ENTHALPY, ENTROPYAND FREE ENERGY 143 5.1. Free Energy of Extraction using Thermodynamical Cycle for Cs+ 146 5.2. Free Energy of Extraction with TMDGA 148 5.3. Free Energy of Extraction using Thermodynamical Cycle with TMDGA 150 5.4. Free Energy of Extraction with CNT-DGA 152 5.5. Free Energy of Extraction using Thermodynamical Cycle 155 6. SEPARATION PARAMETERS -PARTITION COEFFICIENTS 156 6.1. Dual Mode of Extraction for Cs+ and Na+ Ions in Ionic Liquids 159 7. STRUCTURAL AND DYNAMICAL PROPERTIES AT LIQUID-LIQUID INTERFACE 163 7.1. Simulation Methodology 164 7.2. Hydration Structure of DB18C6/Li+ Complex in Water 166 7.3. Dynamic Behaviour of DB18C6/Li+ Complex in Water 167 7.4. Effect of Solvents on the Cation Shielding from Solvent and Relative Stabilities 169 7.5. Dynamics of Li+ and DB18C6 at Interface 172 CONCLUDING REMARKS 175 CONFLICT OF INTEREST 176 ACKNOWLEDGEMENTS 176 REFERENCES 176 Molecular Mechanisms of Cellular Transport, Resistance and Cytotoxic Side Effects of Platinum and Adjuvant Anti-cancer Drugs – A Molecular Orbital Study 196 OBJECTIVES 197 1. INTRODUCTION 197 1.1. Cytotoxic Side Effects 200 1.1.1. Factors that Determine Cytotoxic Side Effects 203 1.2. Resistance to Pt Drugs 214 1.3. Reversal of Resistance to Pt Drugs 219 1.4. Changes to Cell Membranes as a Basis for Reduced Accumulation of Pt in Resistant Cells 225 1.5. Combinatorial Chemotherapeutic Regimes 229 2. RESULTS AND DISCUSSION 231 2.1. Cytotoxic Side Effects 231 2.2. Resistance to Pt Drugs 241 2.3. Reversal of Resistance to Pt Drugs 244 2.4. Combinatorial Regimes and Adjuvant Drugs used with Pt Drugs 250 3. COMPUTATIONAL MOLECULAR ORBITAL METHODS 251 CONCLUSION 253 CONFLICT OF INTEREST 255 ACKNOWLEDGEMENTS 255 REFERENCES 255 Elucidating Allosteric Communications in Proteins via Computational Methods 271 1. INTRODUCTION 272 2. INDUCED FIT VS POPULATION SHIFT PARADIGMS 274 3. WHAT IS ALLOSTERICITY? 276 4. ELUCIDATING ALLOSTERICITY: COLLECTIVE MOTIONS VS. ENERGY TRANSPORT CHANNELS 278 4.1. Graph Theory 281 4.2. Elastic Network Models 290 4.3. Equilibrium and Non-equilibrium Simulations 294 4.4. MC/MD Perturbation Methods 297 4.5. Integration of Graph Theory Techniques with Simulation Based Methods 300 4.6. Statistical Coupling Analysis 303 CONCLUSION 304 CONFLICT OF INTEREST 306 ACKNOWLEDGEMENTS 306 ABBREVIATIONS 306 REFERENCES 308 Information-Theoretic Representation of the Chemical Space of Many Electron Systems 321 1. INTRODUCTION 322 2. INFORMATION-THEORETICAL MEASURES 326 3. INFORMATION-THEORETIC CHEMICAL SPACE FOR MANY ELECTRON SYSTEMS 329 4. CHEMICAL SPACE OF SELECTED BACTERIOSTATIC SULFONAMIDES 336 5. PREDOMINANT INFORMATION QUALITY SCHEME FOR THE ESSENTIAL AMINO ACIDS 342 CONCLUSION 355 DISCLOSURE 357 CONFLICT OF INTEREST 357 ACKNOWLEDGEMENTS 357 REFERENCES 357 SUBJECT INDEX 365 Frontiers in Computational Chemistry presents contemporary research on molecular modeling techniques used in drug discovery and the drug development process: computer aided molecular design, drug discovery and development, lead generation, lead optimization, database management, computer and molecular graphics, and the development of new computational methods or efficient algorithms for the simulation of chemical phenomena including analyses of biological activity. The third volume of this series features four chapters covering in silico approaches to computer aided drug design, modeling of platinum and adjuvant anti-cancer drugs, allostery in proteins and studies on the theory of chemical space in electron systems. Frontiers in Computational Chemistry present contemporary research on molecular modeling techniques used in drug discovery and the drug development process. The Second volume of this series features nine different articles covering topics such as antibact