Innovative approaches in discovery : ethnopharmacology, systems biology, and holistic targeting / Bhushan Patwardhan, Rathnam Chaguturu. – Amsterdam [i pozostałe], copyright © 2017

Spis treści

About the Editors xiii

About the Authors xv

Foreword xxv

Preface xxix

Dedication xxxvii

1. Impasse: Pharmacognosy Holds the Key 1 Rathnam Chaguturu and Bhushan Patwardhan Historical Perspectives 2 Synthetic 3 Ethnopharmacology and Natural Products 3 Emergence of Biotechnology 5 Drug Discovery Process 6 Drug Discovery Impasse 8 New Drug Approvals 9 Drug Recalls and Withdrawals 10 Why Drugs Fail? 12 Need for Novel Approaches 13 Chemical Approaches 14 Approaches 16 Biological Approaches 16 Formulation Discovery 18 Concluding Remarks 19 References 19

2. Why and How Drugs Fail 23 Dada Patil, Bhushan Patwardhan and Kalyani Kumbhare Introduction 23 Drug Withdrawals: Analysis of Six Decades 23 Case Study 1: Statins 25 Discovery and Development of Statins 25 Statin-Induced Diabetes 29 Case Study 2: Example of Troglitazone 31 Mechanism 32 Evidence of 34 TGZ Withdrawals: European and USFDA Responses 37 Cytotoxic Response to Liver Cells: Probable Role of Mitochondrial Injury 38 Inhibition of Bile Salt Export Pump (BSEP) 39 Formation of Electrophilic Reactive Intermediates 41 Role of Host-Related Factors 41 Case Study 3: Example of Rofecoxib 41 Development of Vioxx 42 The Downfall of Vioxx 46 Withdrawal of Vioxx: The "Blockbuster" Drug 47 Rofecoxib and Cardiovascular Toxicity: Role of On-Target, Off-Target, and Intrinsic Chemical Properties 48 Case Study 4: Example of Thalidomide 49 Conclusions and Future Perspectives 51 References 56

3. Holistic Drug Targeting 65 Anuradha Roy and Rathnam Chaguturu Introduction 65 Single-Target Specificity Approach 67 Target Identification and Validation 67 Chemical 68 High-Throughput Screening (HTS) of Druggable Targets 69 Rational 71 Pharmacognosy 72 Target to Lead Bottleneck 73 Biological Redundancy and the Holistic Advantage 73 Approaches for Holistic Drug Targeting 75 Drug Repositioning 78 Combination Therapy 81 Multitarget Drug Discovery 83 Concluding Remarks 85 References 86

4. Reverse Pharmacology 89 Ashwinikumar A. Raut, Mukund S. Chorghade and Ashok D.B. Vaidya Introduction and Background 89 Introduction 89 Background of Reverse Pharmacology 90 The Roots of Modern Drugs in Traditional Remedies/Poisons 91 The Definition of Reverse Pharmacology and Its Different Origins 94 Ayurvedic Pharmacoepidemiology and Observational Therapeutics 95 Ayurvedic Pharmacoepidemiology 96 Observational Therapeutics 97 Clinical Study Designs and Para-Clinical Models in Reverse Pharmacology 98 Ayurveda-lnspired Hits and Leads for New Drug Discoveries 100 Discovery of Natural Products-Based New Chemical Entities via Chemistry and Chemical Biology Technologies 102 Introduction and Background 102 Isolation of Natural Products From Plant Species with Established Indian Folk Properties 105 Design and Synthesis of Natural Product Analogs 106 Reverse Pharmacology and New Domains in Life Sciences 108 Automated Oxidation Chemistry for Diversified Analogues 108 Reverse Pharmacology Approach to GPCR-Focused Drug Discovery 110 Reverse Pharmacology and Novel Biodynamic Actions 111 Unique Dimensions of Ayurveda Therapeutics 112 Organization for Academic Development of Reverse Pharmacology 115 Challenges and Opportunities in Reverse Pharmacology 117 Future Direction and Scope of Differentiation in Reverse Pharmacology 118 References 120

5. Network Pharmacology 127 Uma Chandran, Neelay Mehendale, Saniya Patil, Rathnam Chaguturu and Bhushan Patwardhan Introduction 127 Network Pharmacology 128 Network Biology to Network Pharmacology 129 Network Ethnopharmacology 131 Traditional Medicine Inspired Ethnopharmacological Networks 138 Knowledge Bases for Network Ethnopharmacology 142 Network Construction 144 Ayurveda and Network Ethnopharmacology 146 Network Ethnopharmacology of Triphala 146 Triphala Bioactives 147 Human Proteome and Diseasome Targeting Network of Triphala 147 Microbial Proteome Targeting Network of Triphala 151 Applications of Network Pharmacology 154 Limitations and Solutions 154 Conclusion 157 References 157

6. Genomics-Driven Drug Discovery Process 165 Rathnam Chaguturu Historical Perspective 165 Basic Research Drives Innovation 166 Drug Discovery: Soup to Nuts 167 Target Identification 170 Lead Identification 172 Lead Optimization Strategies 175 Preclinical Studies 179 Preclinical and Clinical Development of Drug Candidates 182 Clinical Development 182 Designing Clinical Trials 183 Clinical Research Phase Studies 183 FDA Review: Registration and Regulatory Approval 184 Phase IV (Life Cycle Management) 184 INDs for Marketed Drugs 184 Concluding Remarks 185 Acknowledgments 185 Appendix 4 189 Forward Chemical Genetics 189 References 191

7. 195 Yogita A. Ghodke-Puranik and Jatinder K. Lamba Introduction 195 Absorption, Distribution, Metabolism, and (ADME) of Drugs 196 Role of ADME Genes in Drug Response and Adverse Drug Reactions 197 Pharmacogenetics in Drug Response 198 Pharmacogenomics of Phase I Drug Metabolizing Enzymes 198 Pharmacogenomics of Phase II Drug Metabolizing Enzymes 207 Pharmacogenomics of Drug Transporters 209 Pharmacogenomics of Drug Targets 212 Genetic Variability Affecting Adverse Drug Reactions 214 Drug-Induced Liver Injury 214 Drug Hypersensitivity 215 Irinotecan-lnduced Myelosuppression 216 Clinical Implementation of Pharmacogenomics 216 Pharmacogenomics in Drug Development 220 Concept of Personalized Medicine in Traditional Indian Medical System: Ayurveda 221 Traditional Medicine to Modern Pharmacogenomics: AyuGenomics 222 Ayugenomics a Tool for Classifying Human Population 223 Ayurveda Prakriti Type Associated With the Metabolic Variability 223 Other Studies on Traditional Medicine 224 Perspectives and Conclusions 225 References 226

8. Transcriptomics and Epigenomics 235 Preeti Chavan-Cautam, Tejas Shah and Kalpana Joshi Introduction 235 Transcriptomics 236 The Interrogation of the Transcriptome 237 Small Interfering RNAs (siRNA), as Therapeutic Agents 237 Challenges 238 The Role of RNAi in Identification and Validation of Drug Targets 240 Applications of RNAi in Various Diseases 241 Applications of Transcriptomics in Drug Discovery 248 Transcriptomics in Herbal Drug Discovery 249 Transcriptomics for Lead Optimization 251 Transcriptomics for Avoiding Toxicity Pathways 252 Transcriptomics in Toxicogenomics 252 Limitations and Further Scope 253 Epigenomics 254 DNA methylation 255 Histone Modifications 255 Epigenomics Methodologies 256 Epigenetic Modifications in Infectious Diseases 257 Epigenetic Modifications in Lifestyle Diseases 258 Epigenetic Modifications in Degenerative Diseases 259 Epigenetic Modifications in Cancer 259 Epigenetic Machinery as Therapeutic Target 260 Epigenomics and Ethnopharmacology 261 Limitations and Scope 262 References 262

9. Proteomics 273 Kalpana Joshi and Dada Patil Introduction 273 Recent Advances in Proteomics Technologies 274 Two-Dimensional Gel Electrophoresis 274 Electrospray Ionization 275 Matrix-Assisted Laser Desorption/lonization 275 Surface-Enhanced Laser Desorption/lonization 275 Protein Microarray Technology 276 Applications of Proteomics in Drug Discovery 276 Biomarker Discovery and Identification of Potential Therapeutic Targets 278 Some Key Examples 278 Understanding Disease Mechanisms—MOA () 279 Proteomics in Lead Optimization 281 Proteomics for Evaluating Drug Toxicity 282 Proteomics in Ethnopharmacology Research 284 Investigating MOA Botanical Drugs 284 Quality Control and Standardization 286 Toxicokinetics and Herb—Drug Interactions 287 Limitations and Future Prospective 288 References 289

10. Chemical Informatics 295 Gerald H. Lushington and Rathnam Chaguturu Key Informatics Challenges in Drug Discovery 297 Efficient Screen Focusing 298 Target Identification 302 Perception 303 Reliable Structure-Activity Relationship (SAR) Elaboration 303 Reliable Structure-Based Design 305 Achieving Target Specificity 308 Accurate Toxicity Prediction 308 Pharmacognosy 310 Conclusions 312 References 313

11. Vaccines and Immunodrugs Discovery 315 Manish Gautam, Bhushan Patwardhan, Sunil Gairola and Suresh Jadhav Introduction 315 Discovery Approaches for Vaccines 316 Empirical Approaches 316 Rational Approach to Discovery 317 Genomic Approaches for Discovery of Antigens 317 Proteomics-Based Approaches 318 Other Technologies 318 Vaccines Against Complex Pathogens 320 Case Study 1: HIV/AIDS Vaccine 320 Why HIV Virus is Challenging 321 Current Approaches for HIV Vaccine 324 Case Study 2: Malaria Vaccine 325 First Successful Malaria Vaccine 326 Challenges to Developing Malaria Vaccines 327 Systems Approach to Vaccinology 327 Examples of Systems Approach 328 Vaccine Adjuvants 329 Immune Targets for Adjuvant Discovery 330 Trends in Adjuvants and Immunomodulators 332 Small-Molecule Immunodrugs 333 Botanicals for Vaccine Adjuvants 334 Saponins as Vaccine Adjuvants 334 Botanically Derived Polysaccharides as Vaccine Adjuvants 335 Discovery Approaches 337 Summary and Conclusion 339 References 340

12. Curcumin, the Holistic Avant-Garde 343 Subash C. Gupta, Ajaikumar B. Kunnumakkara and Bharat B. Aggarwal References 347

13. Safety of Traditional 351 Dnyaneshwar Warude Introduction 351 Conventional Approaches of Quality Control 352 Newer Approaches for Quality 352 Hyphenated Techniques 352 Phyto-Equivalence Studies 355 DNA Markers 355 Approaches in Safety 358 Pharmacogenomics 359 Pharmacovigilance 360 Herb—Drug Interactions 361 Conclusion 362 References 362

14. Holistic Lifestyle 367 Girish Tillu and Bhushan Patwardhan Lifestyle and Behavioral Interventions 369 Emerging Evidence From Research 373 Ayurveda and Yoga 375 to Meditation 378 References 382

15. Collaborative Strategies for Future Drug Discovery 387 Rathnam Chaguturu and Bhushan Patwardhan Prologe 387 The Need 388 Biomedical Ecosystem 389 The New Academia 390 A Roadmap for Successful Drug Discovery in Academia 391 Clinical Models 392 Open Source and Open Science 393 Coordinated, Collaborative Innovation 394 Key Examples 394 Promising Governmental Partnerships 395 Government—Academia—Industry Collaboration: Case From India 396 NMITLI Herbal Drug Project 396 Open Source Drug Discovery 397 Department of Science and Technology 397 Department of Biotechnology 398 SIBRI and BIRAC 398 Indian Council of Medical Research 398 AYUSH 399 Drugs and Biotech Parks 399 Pharma Courting Academia 400 Open Innovations 402 Risk Versus Reward 402 Philanthropic Investments 402 Protection of Intellectual Property 403 Finding the Common Ground 404 It Takes a Village 406 Final Thoughts 408 Further Reading 409

16. Righting the Ship: The Data Reproducibility Conundrum 411 Gerald H. Lushington and Rathnam Chaguturu Navigating Innovation 411 Here Be Monsters: Reducing the Risks 412 Shipwrecks on the Reproducibility Seas 414 Avast Ye Swabs! 415 Shipworms in the Hull: Animal Anomalies, Corrupt Cells, and Reckless RNAi 416 Headstrong Helm: Cognitive Bias 417 Rigging the Sails With Bad Statistics 421 Toward Calmer Waters: Resources and Conclusions 424 Shame on Us! 425 References 426

Index 429

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