دانلود کتاب Structural bioinformatics: applications in preclinical drug discovery

فهرست مطالب :

Preface......Page 6
Contents......Page 8
Editor and Contributors......Page 10
1 Drug Resistance Problem......Page 14
1.1 Overview of the Mechanisms of Drug Resistance......Page 15
1.2 Overview of Computational Methods to Study Drug Resistance......Page 16
2.1 Overview of MD and Conformational Sampling Methods......Page 17
2.2 An Overview of Thermodynamics of Protein–Ligand Binding......Page 19
2.3 Methods to Compute Free Energy Binding......Page 20
2.3.1 End-State Free Energy Methods or Partitioning-Based Methods......Page 21
Molecular Mechanics-Poisson Boltzmann/Generalized Born Surface Area (MM-PB/GB-SA)......Page 22
Linear Interaction Energy (LIE)......Page 23
Free Energy Perturbation (FEP) and Thermodynamic Integration (TI)......Page 24
Alchemical Free Energy Perturbation......Page 26
3.1 Computational Mutation Scanning......Page 27
3.2 MM-PB(GB)-SA......Page 29
3.3 Vitality Analysis......Page 30
Acknowledgements......Page 31
References......Page 32
Abstract......Page 38
1 Introduction......Page 39
2 The Concept of Pharmacophore......Page 40
3 A Typical Pharmacophore Model: Representation of Pharmacophoric Features......Page 41
4 Evolution of the ‘Pharmacophore’ Concept: Historical Perspective......Page 43
5.1 Ligand-Based Pharmacophore Model Generation......Page 45
5.1.2 Conformational Search......Page 46
5.1.3 Feature Extraction and Representation......Page 47
5.2.1 Active Site Identification......Page 48
5.2.3 Generation of Queries, Searching and Hit Analysis......Page 49
5.3.1 Pharmacophore Model Generation with LigandScout......Page 50
5.4 Dynamic Pharmacophore Model Generation and Multicopy Simulations......Page 51
6 Pharmacophore Finger Prints......Page 52
7.1.1 Dynamic E-pharmacophore Models: A Case Study with Mycobacterial CmaA1......Page 53
7.1.3 Pharmacophore Model Validation......Page 54
7.1.5 Pharmacophore-Based Virtual Screening......Page 56
7.2.1 A Case Study with Hexadecahydro-1H-Cyclopenta[a]Phenanthrene Framework (HHCPF)......Page 58
7.3 Target Identification Using Pharmacophore Approaches......Page 59
8 Limitations of Pharmacophore-Based Approaches......Page 60
Acknowledgements......Page 61
References......Page 62
Abstract......Page 67
1 Introduction......Page 68
2 Graph Theory and Residue Interaction Network......Page 69
3.1 Ligand Binding Sites......Page 71
3.2 Protein–Protein Interactions......Page 72
3.3 Allosteric Regulation......Page 73
4 Conclusion......Page 76
References......Page 77
Abstract......Page 82
1 Introduction......Page 83
2.1 Computation of Vertex Index......Page 86
2.2 Rule-Based Activity Prediction......Page 87
2.3 Training Set–Test Set Split......Page 89
2.4 Compound Prioritization......Page 90
2.5 Combinatorial Structure Generation from Root Vertex......Page 91
2.5.1 Structure for a Given Distance Distribution......Page 92
2.5.2 Structure for a Relaxed Distance Distribution......Page 98
3.1.1 Studies with Barbiturates......Page 101
3.1.2 Studies with Nucleoside Analogues......Page 105
3.2.1 Studies with Isoniazid......Page 109
3.2.2 Studies with Streptomycin......Page 110
4 Conclusions and Future Prospect......Page 117
References......Page 118
Abstract......Page 120
1 Introduction......Page 121
1.2 Targets Are More Diverse than Earlier......Page 123
1.3 Starting of Structure-Based Drug Design......Page 124
1.4 Flexibility and Adaptability of Target......Page 126
2.1 Accuracy of Structures......Page 127
2.2 Comparative Homology Modeling and Role of Template......Page 130
2.3 Ligand Flexibility......Page 133
2.4 Protein Flexibility During Binding......Page 134
2.5 Effect of pH on Binding Affinities......Page 138
2.7 Covalent Inhibitors......Page 139
2.8 Functionally Relevant Structure......Page 140
3.1 Identification of Active Site or Binding Site......Page 141
3.2 Characterization of Active Site......Page 143
3.3 Why Different Poses?......Page 146
3.5 Is Estimate of Binding Affinity Sufficient?......Page 148
4.1 Different Types of Scoring Functions......Page 149
4.2 Nonlinear Relation Between IC50 and Score Values......Page 150
5.1 Appropriate Structure of Receptor to Select......Page 151
5.2 Analysis of Docking Tools......Page 154
5.3 Selection of Appropriate Database......Page 156
5.4 Consensus Evaluation of Docking......Page 158
5.5 Selection of Suitable Scoring Function......Page 159
5.6 Consensus Scoring......Page 160
5.7 Inclusion of Flexibility of Ligand and Receptor......Page 161
6 Binding Ability and Free Energy Calculation......Page 162
6.1 Calculation of Enthalpy by MM-PBSA......Page 163
6.2 Effect of Entropy to Ligand Binding......Page 166
6.3 Thermodynamic Methods......Page 168
7 Molecular Recognition and Brownian Dynamics......Page 170
9 Summary......Page 171
References......Page 172
Abstract......Page 187
1 Introduction......Page 188
2.1 P. falciparum ATP-Dependent Heat Shock Protein 90......Page 190
2.2 P. falciparum Phosphatidylinositol 4-kinase (PfPI4€K)......Page 192
2.3 PfNDH2 (P. falciparum NADH-Ubiquinone Oxidoreductase)......Page 193
2.4 P. falciparum Aspartate Carbamoyltransferase (PfACT)......Page 194
2.5 P. falciparum Thioredoxin Reductase (PfTrxR)......Page 195
2.6 P. falciparum Histone Deacetylase (PfHDAC)......Page 196
2.7 P. falciparum Glutathione S-Transferase (PfGST)......Page 198
3.1 Functional Aspects of PfDHODH......Page 199
3.2 Structural Details of PfDHODH......Page 201
3.3 Comparison with DHODH of Other Species......Page 205
3.4 Inhibition of DHODH......Page 207
3.6 Structure-Based Drug Design of PfDHODH inhibitors......Page 208
3.6.1 Benzamide/Naphthamide Derivatives of Anthranilic Acid......Page 209
3.6.2 Diethyl 2-((Arylamino)Methylene) Malonate......Page 210
3.6.3 Triazolopyrimidine......Page 211
3.6.4 N-Alkyl-5-(1H-Benzimidazol-1-yl)Thiophene-2-Carboxamide......Page 214
3.6.6 Dihydrothiophenone Derivatives......Page 217
3.6.7 Thiazole derivatives......Page 218
3.7 Other in Silico Efforts......Page 219
4 Conclusions......Page 224
References......Page 225
Abstract......Page 231
1 Introduction: Drugs and Targets......Page 232
2 Optimization of Drug-Likeness......Page 233
3 Free Energies Relevant to Describe Potency and Pharmacokinetics......Page 234
4 Force-Field-Based Free Energies of Drug Target Binding......Page 236
4.1 Molecular Docking......Page 238
4.2 Success Stories of Force-Field-Based Methods in Drug Discovery Projects......Page 240
5 Ab Initio Methods in Free Energy Calculations......Page 241
5.2 Hybrid QM/MM Approach......Page 242
5.3 Fragment Molecular Orbital......Page 243
5.3.1 Case study: HIV-1 RT RNase H Inhibition Screening......Page 244
5.4 QM Fragmentation Approach......Page 246
6 Entropic Contributions in the QM-Based Free Energy Calculations......Page 249
7.1 Structure-Based ML Approaches in Drug Design......Page 250
7.2 Future Prospects of AI-ML in Drug Design......Page 252
References......Page 253
Abstract......Page 257
1 Introduction......Page 258
2 Overview: Epigenetic Control of Gene Expression......Page 260
3 The First and Second Generation of Epi-Drugs......Page 261
4 Chemoinformatics Study on Epigenetic Modulators......Page 266
5 Conclusion and Future Perspectives......Page 273
References......Page 274
1 Introduction......Page 280
2 Role of X-Ray Crystallography in SBDD and Medicine......Page 282
3 Docking......Page 285
4 Protein Simulation and Drug Designing......Page 288
5 Different Approaches in Drug Designing......Page 294
6.1 Toward Antidotes with PLA2 as Target......Page 300
6.2 Toward Anticancer Compounds with Various Targets......Page 301
6.4 Toward Dengue Virus......Page 302
References......Page 304
Abstract......Page 315
1 Introduction......Page 317
2 Mtb Druggable Target Identification and Validation......Page 320
2.1 Molecular Targets Involved in Cell Wall Biosynthesis and Its Inhibitors......Page 321
2.1.1 Mycolic Acid Biosynthesis Pathway Targets......Page 322
2.1.2 Peptidoglycan Biosynthesis Pathway Targets......Page 323
2.2 Target-Based Drug Design Toward Mtb Regulatory Process......Page 325
2.3 Druggable Targets Involved in Mtb Protein Synthesis......Page 326
2.4 Molecular Targets in Mtb Energy Production and Metabolism......Page 327
2.5 Protein Membrane Transport Targets for Mtb Inhibition......Page 328
2.6 Mycobacterial Drug Targets Involved in Replication and Transcription......Page 329
2.7 Other Druggable Targets of Mtb......Page 330
3 Structure-Based Anti-TB Drug Design Approach and Its Molecular Mechanism of Action......Page 331
4 Recent Computer-Aided Drug Design Approaches for Anti-TB Drug Discovery......Page 338
5 Novel TB Drugs in the Clinical Pipeline......Page 340
6 Future Directions to TB Drug Discovery Process......Page 341
7 Conclusions......Page 344
References......Page 345
Abstract......Page 355
1 Introduction......Page 356
2 Drug Discovery Process......Page 357
3 Big€data Technologies: Challenges and Solutions......Page 359
4 Big€data Technology Components......Page 360
5 Big€data Tools Development for Drug Discovery......Page 364
5.1 Hydrogen Bond Big€data Analytics Tool (HBAT)......Page 365
5.2 Molecular Conformation Generation on Cloud (MOSAIC)......Page 366
5.3 Embarrassingly Parallel Molecular Docking Pipeline......Page 371
5.4 Parallel Molecular Trajectories Visualization & Analytics (DPICT)......Page 372
6 Drug Repurposing Study Using Big€data Analytics......Page 374
7 Latest Development in Big€data......Page 378
References......Page 379
Abstract......Page 383
1 Introduction......Page 384
2 The Single-Particle Cryo-EM at High Resolution......Page 387
2.1 Specimen Preparation for Single-Particle Cryo-EM......Page 388
2.2 Data Collection......Page 389
2.3 Image Processing and Three-Dimensional Reconstruction......Page 392
3.1 Resolution......Page 397
3.3 Validation......Page 398
4 Heterogeneity......Page 399
5 Single-Particle Cryo-EM Applications in SBDD......Page 400
6 Conclusions and Future Prospective......Page 402
References......Page 403
Index......Page 409