Computational Methods for Rational Drug Design

Mithun Rudrapal, PhD, FIC, CChem (India) is Associate Professor at the Department of Pharmaceutical Sciences at Vignan’s Foundation for Science, Technology & Research, Guntur, India. He has over a hundred publications in peer-reviewed international journals and more than a dozen books, including three with Wiley.

List of Contributors xxi

Preface xxvii

1 Molecular Modeling and Drug Design 1
Monalisa Kesh, Abhirup Ghosh, and Diptanil Biswas

1.1 Introduction 1

1.2 Types of Molecular Models 4

1.3 Computational Methods in Drug Discovery 7

1.4 Potential Use and Application of AI in Drug Designing 12

1.5 Limitations of Current Methods 14

1.6 Case Studies 16

1.7 Molecular Docking 17

1.8 Conclusion and Future Works 19

References 20

2 Bioactive Small Molecules and Drug Discovery 25
Ashish Shah, Vaishali Patel, Sathiaseelan Perumal, Riddhi Dave, Neha Zachariah, Ghanshyam Parmar, and Jay Mukesh Chudasama

2.1 Introduction 25

2.2 Importance of Computational Methods in Bioactive Small-Molecules Discovery 26

2.3 Natural Products in Bioactive Small-Molecule Discovery 30

2.4 Role of Density Functional Theory (DFT) Studies in Bioactive Small-Molecule Discovery 33

2.5 Application of DFT to Bioactive Small Molecules 34

2.6 Factors Affecting the Choice of Bioactive Molecules in Drug Discovery 36

2.7 Conclusion 43

References 43

3 Novel Drug Targets for Small Molecule-based Drug Discovery 49
Raghu Ram Achar, Ipsita Panigrahi, Aditi Singh, N. Chandana, and Shivananju Nanjunda Swamy

3.1 Introduction 49

3.2 Drug Target Identification 51

3.3 Classification of Novel Drug Targets 53

3.4 Small Molecules as Drugs 57

3.5 Conclusion 60

References 65

4 Computer-assisted Methods and Tools for Structure- and Ligand-based Drug Design 69
Saurav Kumar Mishra, Sneha Roy, Tabsum Chhetri, and John J. Georrge

4.1 Introduction 69

4.2 Structure-Based Drug Discovery Concept 69

4.3 Ligand-Based Drug Discovery Concept 81

4.4 Structure- and Ligand-Based Assisted Studies 84

4.5 Advancement and Challenges in SBDD and LBDD 90

4.6 Conclusion 90

References 91

5 Virtual Screening and Lead Discovery 97
Nisha Kumari Singh, Nigam Jyoti Maiti, Manshi Mishra, Shantanu Raj, Gourav Rakshit, Rahul Ghosh, and Sharanya Roy

5.1 Introduction to Virtual Screening and Lead Discovery 97

5.2 Molecular Targets and Biomolecular Structures 99

5.3 Virtual Screening Approaches 99

5.4 Databases and Compound Collections 101

5.5 Molecular Docking 102

5.6 Pharmacophore Modeling 104

5.7 Quantitative Structure–Activity Relationship (QSAR) 105

5.8 Machine Learning and AI in Virtual Screening 107

5.9 Hit-to-Lead Optimization 109

5.10 Case Studies and Examples 112

5.11 Challenges and Future Directions 114

5.12 Ethical and Regulatory Considerations 116

5.13 Conclusion 116

References 117

6 ADMET and Physicochemical Assessments in Drug Design 123
Ulviye Acar Çevik, Ayşen Işik, and Abdüllatif Karakaya

6.1 ADMET 123

6.2 Physicochemical Assessments 135

References 144

7 In Silico Modeling and Drug Design 153
Sonali S. Shinde, Sanket S. Rathod, and Sohan S. Chitlange

7.1 Introduction 153

7.2 Target Identification 154

7.3 Computer-Aided Drug Design 156

7.4 ADMET Assessment 160

7.5 Conclusion 160

References 161

8 Pharmacophore Modeling in Drug Design 167
Rahul Ghosh, Sharanya Roy, Gourav Rakshit, Nisha Kumari Singh, and Nigam Jyoti Maiti

8.1 Introduction 167

8.2 Essential Concepts in Pharmacophore Hypothesis Generation 170

8.3 Diverse Approaches to Pharmacophore Modeling 173

8.4 Application of Pharmacophore Modeling 176

8.5 Emerging Trends in Pharmacophore Model Development 180

8.6 Case Studies 183

8.7 Challenges in Pharmacophore Modeling 186

8.8 Conclusion 187

Acknowledgments 188

References 188

9 Scaffold Hopping and De Novo Drug Design 195
Shrimanti Chakraborty, Soumi Chakraborty, Biprajit Sarkar, Rahul Ghosh, Sharanya Roy, Nisha Kumari Singh, and Gourav Rakshit

9.1 Introduction 195

9.2 Scaffold Hopping 196

9.3 De Novo Drug Design 201

9.4 Results and Discussion 211

9.5 Software Tools for SH (Scaffold Hopping) and De Novo Design Selection 214

9.6 Case Study 214

9.7 Conclusion 215

References 216

10 Fragment-based Drug Design and Drug Discovery 221
André M. Oliveira and Mithun Rudrapal

10.1 Introduction 221

10.2 The Process of Finding Fragments 222

10.3 FBDD Strategies 227

10.4 Case Studies 228

10.5 Conclusion and Future Perspectives 230

References 232

11 AI/ML Approaches in Drug Design 237
Kevser Kübra Kırboğa

11.1 Introduction 237

11.2 Traditional Drug Design Methods 237

11.3 AI/ML Landscape in Drug Design 239

11.4 Ethics, Reliability, and Regulatory Issues 244

11.5 Future Directions 246

11.6 Conclusion 247

References 247

12 Network-based Methods in Drug Discovery 255
Ghanshyam Parmar, Ashish Shah, Jay Mukesh Chudasama, Priya Kashav, and Vanesa James

12.1 Introduction 255

12.2 Network Pharmacology: Practical Guide 260

12.3 Ayurveda and Traditional Indian Medicine 269

12.4 Network Pharmacology in Herbal Remedies 273

12.5 Conclusion and Future Prospects 277

References 278

13 Rational Design of Natural Products for Drug Discovery 285
Ankita Kashyap, Anupam Sarma, Bhrigu Kumar Das, and Ashis Kumar Goswami

13.1 Introduction 285

13.2 Natural Products for the Development of New Drugs 286

13.3 Criteria for Selecting Natural Products for Drug Design 288

13.4 Importance of Biodiversity in Sourcing Natural Products 288

13.5 Structural Elucidation of Natural Products 289

13.6 In Silico Computational Tools for Rational Drug Discovery from Natural Sources 290

13.7 Formulation Challenges with Natural Products 298

13.8 Quality by Design (QbD) Approaches 300

13.9 Conclusion 303

References 304

14 Design of Enzyme Inhibitors in Drug Discovery 311
Koyel Kar

14.1 Introduction 311

14.2 Importance of Enzyme Inhibition as a Strategy for Modulating Enzyme Activity 312

14.3 Classification of Enzyme Inhibitors 312

14.4 Strategies Employed in the Design and Development of Enzyme Inhibitors 314

14.5 Limitations and Challenges 321

14.6 Future Directions 321

14.7 Conclusion 322

References 322

15 Rational Design of Peptides and Protein Molecules in Drug Discovery 327
Ipsa Padhy, Abanish Biswas, Chandan Nayak, and Tripti Sharma

15.1 Introduction 327

15.2 Peptides as Therapeutics 328

15.3 New Technologies for Peptide-Based Drug Discovery 344

15.4 Computational Approaches in Peptide Drug Discovery 347

15.5 Conclusion 350

References 351

16 Rational Design of Drugs for Neurodegenerative Disorders 363
Priyanka Kamaria

16.1 Introduction 363

16.2 Common Mechanism of Neurodegeneration 364

16.3 Brief Overview of Computational Methods in Drug Design 365

16.4 Parkinson’s Disease as Prevalent Neurodegenerative Disorder 367

16.5 Conclusion 382

References 382

17 Rational Design of Anti-inflammatory Therapeutics 389
Kratika Singh, Anmol Gupta, Irum Siddiqui, Ashapurna Sinha, Mukesh Kumar Patwa, and Urmila Singh

17.1 Introduction 389

17.2 Navigating Inflammation and its Microenvironment 390

17.3 The Demand for Advanced Anti-inflammatory Medications 393

17.4 Natural Products Used for Anti-inflammatory Drug Development: Systematic Approach in Use of Different Animal Models for Evaluations 394

17.5 Rational Design of Anti-inflammatory Agents 394

17.6 Conclusion and Future Perspectives 397

Authors’ Contribution 397

References 397

18 Rational Design of Antibacterial Agents for Multidrug-Resistant Infections 403
Sathish Kumar Konidala, Podila Naresh, Risy Namratha Jamullamudi, Kamma Harsha Sri, Richie Rashmin Bhandare, and Afzal Basha Shaik

18.1 Introduction 403

18.2 Treatment 404

18.3 Antibacterial Resistance 405

18.4 Medicinal Chemistry Strategies for the Design of Antibacterials Combating Multidrug-Resistant Bacterial Infections 408

18.5 Summary and Conclusion 418

References 418

19 Rational Design of Antiviral Therapeutics 423
Sneha Dokhale, Samiksha Garse, Shine Devarajan, Vaishnavi Thakur, and Shaunak Kolhapure

19.1 Introduction to Antiviral Therapeutics 423

19.2 Targets for Antiviral Therapeutics and Inhibition Strategies 427

19.3 Rational Strategies for Antiviral Therapeutics 431

19.4 Conclusion 437

References 438

20 Rational Design of Anticancer Therapeutics 445
Debarupa Dutta Chakraborty and Prithviraj Chakraborty

20.1 Introduction 445

20.2 Rational Design of Nanomedicine for Cancer Treatment 446

20.3 The CAPIR Cascade: A Nanomedicine Strategy for Administering Cancer Medications 447

20.4 Rational Regulation of Nanoparticle’s Physicochemical Characteristics 447

20.5 Some Approaches of Rational Drug Design in Anticancer Theranostics 448

20.6 Artificial Intelligence’s Progress in Anticancer Drug Development 450

20.7 Conclusion 452

References 452

21 PROTAC and ProTide Strategies in Drug Design 457
Maitreyee Mukherjee

21.1 Introduction 457

21.2 Drug Design: Past to Present 458

21.3 PROTAC Strategy in Drug Design 459

21.4 Emergence of ProTide Technology in Drug Design 465

21.5 Approaches of ProTides in Drug Development 466

21.6 Implementation of ProTides as Nucleoside Analogs 470

21.7 Conclusion 471

References 471

22 Advancing Lung Cancer Treatment Through ALK Receptor-targeted Drug Metabolism and Pharmacokinetics 477
Vivek Yadav, Shikha Goswami, Rajiv Kumar Tonk, and Mithun Rudrapal

22.1 Introduction 477

22.2 ALK Receptor and Its Role 478

22.3 Diagnostic Methods for ALK Rearranged NSCLC 479

22.4 ALK Inhibitors Drug Development 481

22.5 Drug Metabolism of Reported ALK Inhibitor 484

22.6 Resistance and Mutations 487

22.7 Conclusion 488

Conflict of Interest 488

References 489

23 Targeting Intrinsically Disordered Proteins (IDPs) in Drug Discovery: Opportunities and Challenges 493
Sridhar Vemulapalli

23.1 Introduction 493

23.2 Properties and Significance of IDPs 493

23.3 Challenges in Targeting IDPs 496

23.4 Computational Tools for IDP Analysis 499

23.5 Rational Design Approaches for IDP Inhibition 500

23.6 Case Studies 505

23.7 Future Directions 508

23.8 Conclusions 509

References 510

Index 519