{"product_id":"polypharmacology-isbn-9781394182831","title":"Polypharmacology","description":"\u003cp\u003e\u003cb\u003ePractical guide to navigate problems involved with promiscuous ligands and multi-target drug discovery, supported by case studies and real examples\u003c\/b\u003e \u003c\/p\u003e\u003cp\u003e\u003ci\u003ePolypharmacology\u003c\/i\u003e covers the two-sided nature of polypharmacology: its relevance for adverse drug effects, as well as its benefit for certain therapeutic drug classes in effectively treating complex diseases like psychosis and cancer. The book provides practical guidelines and advice to help readers design drugs that have multiple targets while minimizing unwanted off-target effects, discusses important disease areas like viral infection, diabetes, and obesity that have advanced significantly in the last decade, and guides researchers in neighboring areas to polypharmacology. \u003c\/p\u003e\u003cp\u003eThe book is divided into four parts. Part A covers the link between off-targets and adverse drug reactions, how to screen for off-target activity, and how to recognize and optimize compounds with a potential for off-target activity. Part B discusses disease areas which benefit from polypharmacological approaches. Part C highlights important approaches, such as compound design, data mining with web-based tools, and multi-target peptides. Part D provides case study coverage on topics like CDK4\/6 inhibitors for cancer treatment, the potential of multi-target ligands for COVID, and protein degraders and PROTACs. \u003c\/p\u003e\u003cp\u003eSample topics discussed in \u003ci\u003ePolypharmacology\u003c\/i\u003e include: \u003c\/p\u003e\u003cul\u003e\n\u003cli\u003eMolecular properties and structural motifs in pharmacological promiscuity, covering lipophilicity, molecular weight, and other parameters\u003c\/li\u003e\n\u003cli\u003eKinase liabilities in early drug discovery, covering core kinases driving the cell division cycle and consequences of interference, and cell cycle checkpoints controlling cell division\u003c\/li\u003e\n\u003cli\u003eTreatment of major depressive disorder, covering tricyclic antidepressants, monoamine oxidase inhibitors, and selective serotonin and norepinephrine reuptake inhibitors\u003c\/li\u003e\n\u003cli\u003eTrends in the field, such as novel antipsychotics, standardization of screening tools, and the SmartCube System\u003csup\u003e®\u003c\/sup\u003e, as well as lessons from history\u003c\/li\u003e\n\u003c\/ul\u003e \u003cp\u003eDelivering the latest research developments in the field, \u003ci\u003ePolypharmacology\u003c\/i\u003e is an essential reference on the subject for medicinal chemists, pharmacologists, biochemists, computational chemists, and biologists, as well as pharmaceutical professionals involved in drug discovery programs. \u003c\/p\u003e\u003cp\u003eList of Contributors xvii\u003c\/p\u003e \u003cp\u003ePreface xxiii\u003c\/p\u003e \u003cp\u003e\u003cb\u003e1 Introduction 1\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eJürgen Bajorath\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e1.1 Origins 1\u003c\/p\u003e \u003cp\u003e1.2 Pros and Cons 1\u003c\/p\u003e \u003cp\u003e1.3 Discovery and Design 2\u003c\/p\u003e \u003cp\u003e1.4 Structural Data 2\u003c\/p\u003e \u003cp\u003e1.5 Activity Data 3\u003c\/p\u003e \u003cp\u003e1.6 Drug Target Estimates 4\u003c\/p\u003e \u003cp\u003e1.7 Explainable Machine Learning 5\u003c\/p\u003e \u003cp\u003e1.8 Conclusion 6\u003c\/p\u003e \u003cp\u003eReferences 6\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePart A Polypharmacology as a Safety Concern in Drug Discovery 9\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e2 The Safety Relevance and Interpretation of Compound Off-target Interactions 11\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eEric A.G. Blomme, Jonathon R. Green, Prathap Kumar S. Mahalingaiah, Terry R. Van Vleet, and Andy Vo\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e2.1 Introduction 11\u003c\/p\u003e \u003cp\u003e2.2 Assessing Off-Target Interactions of Small Molecules 12\u003c\/p\u003e \u003cp\u003e2.3 Interpretation of Data from Secondary Pharmacology Assays 13\u003c\/p\u003e \u003cp\u003e2.4 Off-Target Interactions of Biologics: Polyreactivity and Polyspecificity 14\u003c\/p\u003e \u003cp\u003e2.5 Case Study Examples 16\u003c\/p\u003e \u003cp\u003e2.6 Physicochemical Properties 18\u003c\/p\u003e \u003cp\u003e2.7 In Silico Methods to Predict Off-Target Interactions 19\u003c\/p\u003e \u003cp\u003e2.8 Predicting Antibody Specificity 19\u003c\/p\u003e \u003cp\u003eReferences 21\u003c\/p\u003e \u003cp\u003e\u003cb\u003e3 Off-target Activity and Adverse Drug Reactions 25\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eDimitar Yonchev\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e3.1 Personal Perspective 25\u003c\/p\u003e \u003cp\u003e3.2 Introduction 25\u003c\/p\u003e \u003cp\u003e3.3 Secondary Pharmacology and Adverse Drug Reactions 26\u003c\/p\u003e \u003cp\u003e3.4 A Practical Perspective 31\u003c\/p\u003e \u003cp\u003eAcknowledgments 33\u003c\/p\u003e \u003cp\u003eReferences 34\u003c\/p\u003e \u003cp\u003e\u003cb\u003e4 Off-Target Screening Strategies 37\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eSonia Roberts and Helen L. Lightfoot\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e4.1 Introduction 37\u003c\/p\u003e \u003cp\u003e4.2 Small Molecules 37\u003c\/p\u003e \u003cp\u003e4.3 Proteolysis-Targeting Chimeras (PROTACs) 39\u003c\/p\u003e \u003cp\u003e4.4 Small Molecules Targeting RNA (smRNA) 41\u003c\/p\u003e \u003cp\u003e4.5 Antisense Oligonucleotides 43\u003c\/p\u003e \u003cp\u003e4.6 Large Molecules 43\u003c\/p\u003e \u003cp\u003e4.7 Regulatory Aspects 44\u003c\/p\u003e \u003cp\u003e4.8 Future Outlook 45\u003c\/p\u003e \u003cp\u003eAcknowledgments 45\u003c\/p\u003e \u003cp\u003eAddendum 45\u003c\/p\u003e \u003cp\u003eReferences 45\u003c\/p\u003e \u003cp\u003e\u003cb\u003e5 Molecular Properties and Structural Motifs Related to Pharmacological Promiscuity 49\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eJens-Uwe Peters\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e5.1 Introduction 49\u003c\/p\u003e \u003cp\u003e5.2 Basicity and Protonation State 49\u003c\/p\u003e \u003cp\u003e5.3 Lipophilicity 52\u003c\/p\u003e \u003cp\u003e5.4 Molecular Weight 54\u003c\/p\u003e \u003cp\u003e5.5 Other Parameters 54\u003c\/p\u003e \u003cp\u003e5.6 Structural Motifs 54\u003c\/p\u003e \u003cp\u003e5.7 Conclusion 56\u003c\/p\u003e \u003cp\u003eReferences 57\u003c\/p\u003e \u003cp\u003e\u003cb\u003e6 Kinase Liabilities in Early Drug Discovery 61\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eStephan Kirchner\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e6.1 Introduction 61\u003c\/p\u003e \u003cp\u003e6.2 Protein Kinases and Inhibitor Binding Sites 61\u003c\/p\u003e \u003cp\u003e6.3 Kinase-regulated Cardiac Functions and Potential Consequences of Inhibition 64\u003c\/p\u003e \u003cp\u003e6.4 Core Kinases Driving the Cell Division Cycle and Consequences of Interference 64\u003c\/p\u003e \u003cp\u003e6.5 Cell Cycle Checkpoints Controlling Cell Division 69\u003c\/p\u003e \u003cp\u003e6.6 Selectivity Profiling of Kinase Inhibition 71\u003c\/p\u003e \u003cp\u003eReferences 72\u003c\/p\u003e \u003cp\u003e\u003cb\u003e7 Activity at Cardiovascular Ion Channels 77\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eIan M. Bell and Armando A. Lagrutta\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e7.1 Introduction 77\u003c\/p\u003e \u003cp\u003e7.2 Screening Methods 79\u003c\/p\u003e \u003cp\u003e7.3 Structural Insights into the Interaction Between Drugs and CV Ion Channels 80\u003c\/p\u003e \u003cp\u003e7.4 Medicinal Chemistry Approaches 85\u003c\/p\u003e \u003cp\u003e7.5 Conclusion 90\u003c\/p\u003e \u003cp\u003eReferences 91\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePart B Polypharmacology as an Opportunity in Different Disease Areas 97\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e8 Toward Mechanism-based Therapies and Network Pharmacology 99\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eCristian Nogales, Zina Piper, Zeinab Mamdouh, and Mayra Pacheco Pachado\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e8.1 A Crisis in the Pharmaceutical Industry 99\u003c\/p\u003e \u003cp\u003e8.2 Disease Modules as Targets for Precision Medicine 99\u003c\/p\u003e \u003cp\u003e8.3 Mechanism-based Therapies and Network Pharmacology 101\u003c\/p\u003e \u003cp\u003e8.4 Implementing Mechanism-based Therapies 103\u003c\/p\u003e \u003cp\u003e8.5 Summary and Conclusions 105\u003c\/p\u003e \u003cp\u003eReferences 106\u003c\/p\u003e \u003cp\u003e\u003cb\u003e9 Advancements in Rational Multi-Targeted Drug Discovery 109\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eBalaguru Ravikumar, Anna Cichońska, Navriti Sahni, Tero Aittokallio, and Rayees Rahman\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e9.1 Introduction 109\u003c\/p\u003e \u003cp\u003e9.2 Cancer and the Existing Treatment Strategies 109\u003c\/p\u003e \u003cp\u003e9.3 Safety and Efficacy: A Double-Edged Sword 114\u003c\/p\u003e \u003cp\u003e9.4 Rational Design of MTDs 116\u003c\/p\u003e \u003cp\u003e9.5 Perspective, Limitations, and Challenges 120\u003c\/p\u003e \u003cp\u003eReferences 120\u003c\/p\u003e \u003cp\u003e\u003cb\u003e10 Polypharmacology 127\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eLynn L. Silver\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e10.1 Introduction 127\u003c\/p\u003e \u003cp\u003e10.2 The Failure of Single-target-based Discovery of Antibiotics 127\u003c\/p\u003e \u003cp\u003e10.3 Attempts at Purposeful Multitargeting 128\u003c\/p\u003e \u003cp\u003e10.4 Cell Surface Targets and Macrocyclic Peptides (MCPs) 131\u003c\/p\u003e \u003cp\u003e10.5 Conclusions 136\u003c\/p\u003e \u003cp\u003eReferences 136\u003c\/p\u003e \u003cp\u003e\u003cb\u003e11 Multi-Specific Binding Strategy 141\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eYang Zhou, Shujing Xu, Dang Ding, Kai Tang, Xinyong Liu, Meehyein Kim, and Peng Zhan\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e11.1 Proteolysis Targeting Chimera (PROTAC) 142\u003c\/p\u003e \u003cp\u003e11.2 Antibody Recruiting Molecules 147\u003c\/p\u003e \u003cp\u003e11.3 Antibody-Drug Conjugates (ADCs) 150\u003c\/p\u003e \u003cp\u003e11.4 Antiviral Drug Delivery Systems 151\u003c\/p\u003e \u003cp\u003e11.5 Ribonuclease Targeting Chimeras 155\u003c\/p\u003e \u003cp\u003e11.6 Other Bifunctional Small Molecules 157\u003c\/p\u003e \u003cp\u003e11.7 Summary and Outlook 159\u003c\/p\u003e \u003cp\u003eReferences 160\u003c\/p\u003e \u003cp\u003e\u003cb\u003e12 Polypharmacology for the Treatment of Major Depressive Disorder 165\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eTiffany Schwasinger-Schmidt\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e12.1 Introduction 165\u003c\/p\u003e \u003cp\u003e12.2 Multitargeted Antidepressants 166\u003c\/p\u003e \u003cp\u003e12.3 Conclusions 170\u003c\/p\u003e \u003cp\u003eReferences 171\u003c\/p\u003e \u003cp\u003e\u003cb\u003e13 Multi-target Drugs to Treat Metabolic Diseases 175\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eFelix F. Lillich, Samaneh Goorani, Ewgenij Proschak, and John D. Imig\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e13.1 Introduction 175\u003c\/p\u003e \u003cp\u003e13.2 Metabolic Diseases and Current Treatment Approaches 175\u003c\/p\u003e \u003cp\u003e13.3 Strategies to Develop Multi-target Drugs for Metabolic Diseases 177\u003c\/p\u003e \u003cp\u003e13.4 Approaches Involving Modulation of PPARs and Other Metabolically Relevant Nuclear Receptors 180\u003c\/p\u003e \u003cp\u003e13.5 Approaches Involving Inhibition of DPP4 181\u003c\/p\u003e \u003cp\u003e13.6 Diverse Target Combinations for Polypharmacological Treatment of Metabolic Disorders 183\u003c\/p\u003e \u003cp\u003e13.7 Conclusion 184\u003c\/p\u003e \u003cp\u003eReferences 185\u003c\/p\u003e \u003cp\u003e\u003cb\u003e14 Overcoming the Challenges of Multi-Target-Directed Ligands for Alzheimer’s Disease 193\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eElisa Uliassi, Anna M. Pasieka, Eleonora Diamanti, and Maria Laura Bolognesi\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e14.1 Introduction 193\u003c\/p\u003e \u003cp\u003e14.2 Target Identification: In the Search for New Target Pairs 193\u003c\/p\u003e \u003cp\u003e14.3 PK Challenges in MTDL Optimization 195\u003c\/p\u003e \u003cp\u003e14.4 Phenotypic Screening: In a Search for an Early Proof-of-Concept 197\u003c\/p\u003e \u003cp\u003e14.5 Conclusions 199\u003c\/p\u003e \u003cp\u003eReferences 199\u003c\/p\u003e \u003cp\u003e\u003cb\u003e15 The Role of Polypharmacology in the History of Drug Discovery 203\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eAxel Helmstaedter\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e15.1 Introduction: Drug Discovery in the Twentieth Century 203\u003c\/p\u003e \u003cp\u003e15.2 Natural Products 205\u003c\/p\u003e \u003cp\u003e15.3 Historical Drugs with Multiple Actions 206\u003c\/p\u003e \u003cp\u003e15.4 From Serendipity to Concept: Repurposing and Polypharmacology 209\u003c\/p\u003e \u003cp\u003eReferences 210\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePart C How to Discover Polypharmacological Drugs 213\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e16 Strategies for Multi-target Drug Discovery 215\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eDayong Shi and Xiangqian li\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e16.1 Introduction 215\u003c\/p\u003e \u003cp\u003e16.2 Rational Design of Multitargeted Ligands 215\u003c\/p\u003e \u003cp\u003e16.3 Discussion and Conclusion 220\u003c\/p\u003e \u003cp\u003eReferences 220\u003c\/p\u003e \u003cp\u003e\u003cb\u003e17 Predicting Polypharmacology with Web-Based Tools 223\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eMaedeh Darsaraee, Sacha Javor, and Jean-Louis Reymond\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e17.1 Introduction 223\u003c\/p\u003e \u003cp\u003e17.2 Pass 223\u003c\/p\u003e \u003cp\u003e17.3 Sea 226\u003c\/p\u003e \u003cp\u003e17.4 Super-PRED 226\u003c\/p\u003e \u003cp\u003e17.5 TargetHunter 227\u003c\/p\u003e \u003cp\u003e17.6 SwissTargetPrediction 227\u003c\/p\u003e \u003cp\u003e17.7 TargetNet 229\u003c\/p\u003e \u003cp\u003e17.8 PPB 229\u003c\/p\u003e \u003cp\u003e17.9 PPB2 230\u003c\/p\u003e \u003cp\u003e17.10 Comparison of Different Web-Based Tools 231\u003c\/p\u003e \u003cp\u003e17.11 Conclusion 233\u003c\/p\u003e \u003cp\u003eAcknowledgement 233\u003c\/p\u003e \u003cp\u003eReferences 233\u003c\/p\u003e \u003cp\u003e\u003cb\u003e18 Using Phenotypic Screening to Uncover the Full Potential of Polypharmacology 237\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eArsenio Nueda\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e18.1 Introduction: Phenotypic Screening and Phenotypic Drug Discovery 237\u003c\/p\u003e \u003cp\u003e18.2 Polypharmacology Discovered Using Phenotypic Screening 239\u003c\/p\u003e \u003cp\u003e18.3 PDD Strategies to Discover Novel Polypharmacology 240\u003c\/p\u003e \u003cp\u003e18.4 Optimizing Polypharmacology in Phenotypic Screening Hits 242\u003c\/p\u003e \u003cp\u003e18.5 Understanding the MoA from a PDD and Polypharmacology Perspectives 245\u003c\/p\u003e \u003cp\u003e18.6 The Path to Virtual PDD-Derived Polypharmacology 246\u003c\/p\u003e \u003cp\u003e18.7 Conclusions and Future Directions 246\u003c\/p\u003e \u003cp\u003eReferences 248\u003c\/p\u003e \u003cp\u003e\u003cb\u003e19 Phenotypic Polypharmacology Drug Discovery for CNS Applications 251\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eAlberto Ambesi-Impiombato, Lee McDermott, Alan Lars Pehrson, and Daniela Brunner\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e19.1 Introduction 251\u003c\/p\u003e \u003cp\u003e19.2 BPDD Lessons from the History of Psychopharmacology 251\u003c\/p\u003e \u003cp\u003e19.3 Current Trends in Psychopharmacology 253\u003c\/p\u003e \u003cp\u003e19.4 A Machine Learning-Based System for Global Behavior Profiling for CNS Drug Discovery 255\u003c\/p\u003e \u003cp\u003e19.5 Modeling Chemical and Phenotypic Relationships of Compounds Screened in SmartCube® 257\u003c\/p\u003e \u003cp\u003e19.6 Privileged Scaffolds and BPDD with SmartCube® 260\u003c\/p\u003e \u003cp\u003e19.7 Ulotaront (SEP-363856) a BPDD Case Study 261\u003c\/p\u003e \u003cp\u003e19.8 Conclusions 262\u003c\/p\u003e \u003cp\u003eReferences 263\u003c\/p\u003e \u003cp\u003eAppendix 266\u003c\/p\u003e \u003cp\u003e\u003cb\u003e20 Multi-target Peptides for the Treatment of Metabolic Diseases 269\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eMartin Bossart and Gerhard Hessler\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e20.1 Introduction 269\u003c\/p\u003e \u003cp\u003e20.2 Glucagon-like Peptide-1 (GLP-1) Receptor Agonists 269\u003c\/p\u003e \u003cp\u003e20.3 Unimolecular Multiagonists Based on Glucagon-like Peptide-1 (GLP-1) Following the One-pharmacophore Approach 270\u003c\/p\u003e \u003cp\u003e20.4 GLP-1 Receptor\/Glucagon Receptor Dual Agonists 272\u003c\/p\u003e \u003cp\u003e20.5 Clinical Advanced GLP-1\/GCGR Dual Agonists 275\u003c\/p\u003e \u003cp\u003e20.6 GLP-1 Receptor\/Glucose-dependent Insulinotropic Polypeptide (GIP) Receptor Dual Agonists 277\u003c\/p\u003e \u003cp\u003e20.7 GLP-1 Receptor\/Glucagon Receptor\/GIP Receptor Triple Agonists 279\u003c\/p\u003e \u003cp\u003e20.8 Further Unimolecular Multiagonists Based on Glucagon-like Peptide-1 (GLP-1) Following the One-pharmacophore Approach 280\u003c\/p\u003e \u003cp\u003e20.9 Unimolecular Multiagonists Based on Glucagon-like Peptide-1 (GLP-1) Following the Two-pharmacophore Approach 282\u003c\/p\u003e \u003cp\u003e20.10 Conclusion 284\u003c\/p\u003e \u003cp\u003eReferences 284\u003c\/p\u003e \u003cp\u003e\u003cb\u003e21 The SOSA Approach to Drug Discovery 289\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eNorbert Handler, Michal Poznik, and Helmut Buschmann\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e21.1 Introduction 289\u003c\/p\u003e \u003cp\u003e21.2 Definition, Rational, and Concept of the SOSA Approach 290\u003c\/p\u003e \u003cp\u003e21.3 Drugs in Other Drugs: Drug as Fragments 291\u003c\/p\u003e \u003cp\u003e21.4 Old Drugs 292\u003c\/p\u003e \u003cp\u003e21.5 The SOSA Approach and Analog Design 292\u003c\/p\u003e \u003cp\u003e21.6 Patentability and Interference Risk of the SOSA Approach 293\u003c\/p\u003e \u003cp\u003e21.7 Case Studies and Examples 296\u003c\/p\u003e \u003cp\u003e21.8 Conclusion 312\u003c\/p\u003e \u003cp\u003eCredit 313\u003c\/p\u003e \u003cp\u003eReferences 313\u003c\/p\u003e \u003cp\u003e\u003cb\u003ePart D Polypharmacology, Classic Case Studies and Recent Research 319\u003c\/b\u003e\u003c\/p\u003e \u003cp\u003e\u003cb\u003e22 Dual Inhibitors of CDK4\/6 for Treating Cancer 321\u003cbr\u003e \u003c\/b\u003e\u003ci\u003ePeter L. Toogood\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e22.1 Introduction 321\u003c\/p\u003e \u003cp\u003e22.2 Selectivity Profile of Approved CDK4\/6 Inhibitors 321\u003c\/p\u003e \u003cp\u003e22.3 Clinical Experience with CDK4\/6 Inhibitors 325\u003c\/p\u003e \u003cp\u003e22.4 New Approaches and Agents for CDK4\/6 Inhibition 330\u003c\/p\u003e \u003cp\u003e22.5 Conclusion 331\u003c\/p\u003e \u003cp\u003eAcknowledgment 332\u003c\/p\u003e \u003cp\u003eReferences 332\u003c\/p\u003e \u003cp\u003e\u003cb\u003e23 Tapentadol, a Clinically Proven Analgesic with Two Mechanisms 339\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eThomas Christoph, Helmut Buschmann, Norbert Handler, and Michal Poznik\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e23.1 Introduction 339\u003c\/p\u003e \u003cp\u003e23.2 The Discovery of Tapentadol – From Morphine and Tramadol to the Discovery of Tapentadol 339\u003c\/p\u003e \u003cp\u003e23.3 Pharmacokinetics of Tapentadol 342\u003c\/p\u003e \u003cp\u003e23.4 The Polymorphic Forms of Tapentadol Hydrochloride 343\u003c\/p\u003e \u003cp\u003e23.5 Pharmaceutical Salts of Tapentadol 344\u003c\/p\u003e \u003cp\u003e23.6 Synthesis Routes to Tapentadol Hydrochloride 354\u003c\/p\u003e \u003cp\u003e23.7 The Pharmacological Profile of Tapentadol as a Multiple Ligand for the Treatment of Several Types of Pain 356\u003c\/p\u003e \u003cp\u003e23.8 Summary 363\u003c\/p\u003e \u003cp\u003eReferences 363\u003c\/p\u003e \u003cp\u003e\u003cb\u003e24 Thalidomide – From a Banned Drug to Molecular Glues, PROTACs, and New Concepts in Drug Discovery 367\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eJunichi Yamamoto, Hiroshi Handa, and Yuki Yamaguchi\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e24.1 Introduction 367\u003c\/p\u003e \u003cp\u003e24.2 Thalidomide History: From Tragedy to Therapeutic Revival 367\u003c\/p\u003e \u003cp\u003e24.3 Polypharmacology of Thalidomide and its Derivatives 370\u003c\/p\u003e \u003cp\u003e24.4 Structural Understanding of the Mechanisms of Action of CELMoDs 374\u003c\/p\u003e \u003cp\u003e24.5 Challenges and Future Perspectives in the Development of CELMoDs 377\u003c\/p\u003e \u003cp\u003e24.6 Conclusions 379\u003c\/p\u003e \u003cp\u003eReferences 379\u003c\/p\u003e \u003cp\u003e\u003cb\u003e25 The Polypharmacology of Cariprazine and its Implications to Clinical Indications 385\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eAttila Egyed, Dóra J. Kiss, and György M. Keserű\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e25.1 Introduction 385\u003c\/p\u003e \u003cp\u003e25.2 Structure and Binding 386\u003c\/p\u003e \u003cp\u003e25.3 The Role of the Primary and Secondary Pharmacophore in Binding and Selectivity 387\u003c\/p\u003e \u003cp\u003e25.4 Cariprazine–Functional Profile, Polypharmacology, and Functional Selectivity 389\u003c\/p\u003e \u003cp\u003e25.5 In Vivo Profile of Cariprazine 390\u003c\/p\u003e \u003cp\u003e25.6 Cariprazine in Clinical Practice 393\u003c\/p\u003e \u003cp\u003e25.7 Conclusions 395\u003c\/p\u003e \u003cp\u003eReferences 396\u003c\/p\u003e \u003cp\u003e\u003cb\u003e26 Multi-Targeted Antivirals 405\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eBing Ye, Letian Song, Meehyein Kim, Shenghua Gao, Peng Zhan, and Xinyong Liu\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e26.1 Multi-Target Inhibitors Targeting Both SARS-CoV-2 and Host Proteins 405\u003c\/p\u003e \u003cp\u003e26.2 Multi-Target Inhibitors Directly Targeting SARS-CoV- 2 411\u003c\/p\u003e \u003cp\u003e26.3 Summary and Prospect 417\u003c\/p\u003e \u003cp\u003eAcknowledgments 418\u003c\/p\u003e \u003cp\u003eReferences 418\u003c\/p\u003e \u003cp\u003e\u003cb\u003e27 Multi-target Antimalarials as a Strategy to Reduce Resistance Risk 423\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eLauren B. Coulson and Kelly Chibale\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e27.1 Introduction 423\u003c\/p\u003e \u003cp\u003e27.2 Next-generation Antimalarials 424\u003c\/p\u003e \u003cp\u003e27.3 Resistance Risk as a Criterion for the Prioritization of New Molecules and Targets 424\u003c\/p\u003e \u003cp\u003e27.4 Polypharmacology in Malaria Drug Discovery 426\u003c\/p\u003e \u003cp\u003e27.5 Concluding Remarks and the Way Forward 432\u003c\/p\u003e \u003cp\u003eReferences 432\u003c\/p\u003e \u003cp\u003e\u003cb\u003e28 Multi-target Compounds for Tuberculosis 437\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eGiovanni Stelitano, Mario Cocorullo, and Laurent R. Chiarelli\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e28.1 Tuberculosis and the Problem of Antimicrobial Resistance 437\u003c\/p\u003e \u003cp\u003e28.2 Polypharmacology to Fight M. tuberculosis Antimicrobial Resistance 438\u003c\/p\u003e \u003cp\u003e28.3 Multitarget Compounds Against TB 439\u003c\/p\u003e \u003cp\u003e28.4 Multitarget Compounds Against TB-HIV Co-infection 443\u003c\/p\u003e \u003cp\u003e28.5 Conclusions 445\u003c\/p\u003e \u003cp\u003eReferences 445\u003c\/p\u003e \u003cp\u003e\u003cb\u003e29 Dual-acting HIV Inhibitors 451\u003cbr\u003e \u003c\/b\u003e\u003ci\u003eMaría-José Camarasa, Ana-Rosa San-Félix, and Sonia de Castro\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003e29.1 Introduction 451\u003c\/p\u003e \u003cp\u003e29.2 HIV and Hepatitis Viruses Co-infections 451\u003c\/p\u003e \u003cp\u003e29.3 Compounds with Dual Activity Against HIV and EV-A 71 456\u003c\/p\u003e \u003cp\u003eAcknowledgement 458\u003c\/p\u003e \u003cp\u003eReferences 458\u003c\/p\u003e \u003cp\u003e\u003cb\u003e30 Multi-kinase Inhibitors for the Treatment of Pancreatic Cancer 463\u003cbr\u003e \u003c\/b\u003e\u003ci\u003ePaul Dent and Andrew Poklepovic\u003c\/i\u003e\u003c\/p\u003e \u003cp\u003eAcknowledgements 467\u003c\/p\u003e \u003cp\u003eReferences 467\u003c\/p\u003e \u003cp\u003eIndex 469\u003c\/p\u003e  \u003cp\u003e\u003cb\u003eJens-Uwe Peters, PhD\u003c\/b\u003e is a Director of Medicinal Chemistry at Skyhawk Therapeutics, and he previously worked at Idorsia Pharmaceuticals and Roche. He has extensive experience with drug discovery projects and safety profiling. He edited the book \u003ci\u003ePolypharmacology in Drug Discovery\u003c\/i\u003e (Wiley 2012).   \u003c\/p\u003e\u003cp\u003e\u003cb\u003ePractical guide to navigate problems involved with promiscuous ligands and multi-target drug discovery, supported by case studies and real examples\u003c\/b\u003e \u003c\/p\u003e\u003cp\u003e\u003ci\u003ePolypharmacology\u003c\/i\u003e covers the two-sided nature of polypharmacology: its relevance for adverse drug effects, as well as its benefit for certain therapeutic drug classes in effectively treating complex diseases like psychosis and cancer. The book provides practical guidelines and advice to help readers design drugs that have multiple targets while minimizing unwanted off-target effects, discusses important disease areas like viral infection, diabetes, and obesity that have advanced significantly in the last decade, and guides researchers in neighboring areas to polypharmacology. \u003c\/p\u003e\u003cp\u003eThe book is divided into four parts. Part A covers the link between off-targets and adverse drug reactions, how to screen for off-target activity, and how to recognize and optimize compounds with a potential for off-target activity. Part B discusses disease areas which benefit from polypharmacological approaches. Part C highlights important approaches, such as compound design, data mining with web-based tools, and multi-target peptides. Part D provides case study coverage on topics like CDK4\/6 inhibitors for cancer treatment, the potential of multi-target ligands for COVID, and protein degraders and PROTACs. \u003c\/p\u003e\u003cp\u003eSample topics discussed in \u003ci\u003ePolypharmacology\u003c\/i\u003e include: \u003c\/p\u003e\u003cul\u003e\n\u003cli\u003eMolecular properties and structural motifs in pharmacological promiscuity, covering lipophilicity, molecular weight, and other parameters\u003c\/li\u003e\n\u003cli\u003eKinase liabilities in early drug discovery, covering core kinases driving the cell division cycle and consequences of interference, and cell cycle checkpoints controlling cell division\u003c\/li\u003e\n\u003cli\u003eTreatment of major depressive disorder, covering tricyclic antidepressants, monoamine oxidase inhibitors, and selective serotonin and norepinephrine reuptake inhibitors\u003c\/li\u003e\n\u003cli\u003eTrends in the field, such as novel antipsychotics, standardization of screening tools, and the SmartCube System\u003csup\u003e®\u003c\/sup\u003e, as well as lessons from history\u003c\/li\u003e\n\u003c\/ul\u003e \u003cp\u003eDelivering the latest research developments in the field, \u003ci\u003ePolypharmacology\u003c\/i\u003e is an essential reference on the subject for medicinal chemists, pharmacologists, biochemists, computational chemists, and biologists, as well as pharmaceutical professionals involved in drug discovery programs.\u003c\/p\u003e","brand":"Wiley","offers":[{"title":"Default Title","offer_id":47989813706981,"sku":"NP9781394182831","price":250.0,"currency_code":"USD","in_stock":false}],"thumbnail_url":"\/\/cdn.shopify.com\/s\/files\/1\/1842\/7735\/files\/9781394182831.jpg?v=1761785554","url":"https:\/\/k12savings.com\/products\/polypharmacology-isbn-9781394182831","provider":"K12savings","version":"1.0","type":"link"}