POLYPHARMACOLOGY IN DRUG DISCOVERY -- CONTENTS -- CONTRIBUTORS -- PREFACE -- Introduction: The Case for Polypharmacology -- PART A POLYPHARMACOLOGY: A SAFETY CONCERN IN DRUG DISCOVERY -- 1. The Relevance of Off-Target Polypharmacology -- 2. Screening for Safety-Relevant Off-Target Activities -- 2.1 Introduction -- 2.2 General Aspects -- 2.2.1 Rationale for Profiling Molecules for Potential Adverse Effects -- 2.2.2 When to Profile or Screen for Safety? -- 2.2.3 How Safety Profiling is Performed -- 2.3 Selection of Off Targets -- 2.3.1 Selection Criteria for Off Targets -- 2.3.2 Hierarchical Profiling: Primary, Secondary, and Follow-up Testing -- 2.3.3 Organ-Specific Panels -- 2.3.4 Functional Considerations -- 2.3.5 Pharmacological Promiscuity -- 2.3.6 Validation with Marketed Drugs -- 2.4 In Silico Approaches to (Off-Target) Profiling -- 2.5 Summary and Conclusions -- References -- 3. Pharmacological Promiscuity and Molecular Properties -- 3.1 Introduction: Pharmacological Promiscuity in the History of Drug Discovery -- 3.2 Lipophilicity -- 3.3 Molecular Weight -- 3.4 Ionization State -- 3.5 Other Molecular Descriptors and Structural Motifs -- 3.6 Implications for Drug Discovery -- References -- 4. Kinases as Antitargets in Genotoxicity -- 4.1 Protein Kinases and Inhibitor-Binding Sites -- 4.2 Cyclin-Dependent Kinases Controlling Unregulated Cell Proliferation -- 4.3 Mitotic Kinases as Guardians Protecting Cells from Aberrant Chromosome Segregation -- 4.4 Conclusion -- References -- 5. Activity at Cardiovascular Ion Channels: A Key Issue for Drug Discovery -- 5.1 Introduction -- 5.2 Screening Methods -- 5.3 Structural Insights into the Interaction Between Drugs and Cardiovascular Ion Channels -- 5.4 Medicinal Chemistry Approaches -- 5.5 Conclusion -- References -- 6. Prediction of Side Effects Based on Fingerprint Profiling and Data Mining.

6.1 Introduction to BioPrint -- 6.1.1 Compounds -- 6.1.2 Assays -- 6.2 The Pharmacological Fingerprint -- 6.3 Antidepressant Example -- 6.4 Profile Similarity at Nontherapeutic Targets -- 6.5 Interpreting the Polypharmacology Profile -- 6.5.1 Interpretation on a Hit-by-Hit Basis -- 6.5.2 Analyzing the Entire Profile -- 6.6 Methods -- 6.7 Patterns of Activity -- 6.8 Integrating Function Profile Data with Traditional Pharmacological Binding Data -- 6.9 Analysis of the Antifungal Tioconazole -- 6.10 Conclusions -- References -- PART B POLYPHARMACOLOGY: AN OPPORTUNITY FOR DRUG DISCOVERY -- 7. Polypharmacological Drugs: "Magic Shotguns" for Psychiatric Diseases -- 7.1 Introduction -- 7.2 Definition -- 7.3 Discovery and Extent of Promiscuity Among Psychiatric Drugs -- 7.4 Why are So Many Psychiatric Drugs Promiscuous? -- 7.4.1 Multiplicity and Similarity of Targets -- 7.4.2 Other Factors -- 7.5 Conclusions -- References -- 8. Polypharmacological Kinase Inhibitors: New Hopes for Cancer Therapy -- 8.1 Targeted Therapies: A New Era in the Treatment of Cancer -- 8.2 Single-Targeted Therapy -- 8.2.1 Oncogene Addiction: A Rationale for Selective Therapies -- 8.2.2 Disadvantages of Single Targeting: The Other Side of the Coin -- 8.3 From Single- to Multitargeted Drugs in Cancer Therapy -- 8.3.1 The Tumor-Stroma Connection -- 8.3.2 Advantages of Multitargeting -- 8.4 Polypharmacology Kinase Inhibitors in Clinical Practice and Under Development -- 8.4.1 Sunitinib -- 8.4.2 Sorafenib -- 8.4.3 Pazopanib -- 8.4.4 Axitinib -- 8.4.5 Vandetanib -- 8.5 Concluding Remarks -- References -- 9. Polypharmacology as an Emerging Trend in Antibacterial Discovery -- 9.1 Introduction -- 9.1.1 Implications of the Benefit of Multitargeting on Antibacterial Discovery -- 9.1.2 Combinations -- 9.2 Classical Antibacterial Polypharmacology -- 9.2.1 b-Lactams -- 9.2.2 Fluoroquinolones.

9.2.3 Cycloserine -- 9.2.4 Special Case: rRNA -- 9.3 New Approaches to Multitargeted Single Pharmacophores -- 9.3.1 Nonfluoroquinolone Dual Targeting of Gyrase and Topoisomerase IV -- 9.3.2 DNA Pol III C and E -- 9.3.3 Bacterial Fatty Acid Synthesis -- 9.3.3.1 Enoyl Reductases -- 9.3.3.2 Ketoacyl ACP Synthases -- 9.3.4 A Pterin Derivative as an Inhibitor of DHPS and DHFR -- 9.4 Synthetic Lethals -- 9.4.1 Ef-Tu: Duplicate Genes in Gram Negatives -- 9.4.2 Finding New Synthetic Lethals -- 9.5 Hybrid Molecules -- 9.6 Conclusions -- References -- 10. A "Magic Shotgun" Perspective on Anticonvulsant Mechanisms -- 10.1 Introduction -- 10.2 Anticonvulsant Mechanism -- 10.3 Defining Promiscuity -- 10.4 Lessons for Promiscuity -- 10.4.1 Lessons from Endogenous Signaling -- 10.4.2 Lessons from Anticonvulsant Electrophysiology -- 10.5 Use of Anticonvulsants in Disorders other than Epilepsy -- 10.6 Experimental and Theoretical Support for a "Magic Shotgun" Approach -- 10.7 Current Multitarget Strategies -- 10.8 Practical Considerations -- 10.9 Conclusion -- References -- 11. Selective Optimization of Side Activities (SOSA): A Promising Way for Drug Discovery -- 11.1 Introduction -- 11.2 Definition and Principle -- 11.3 Rationale of SOSA -- 11.4 Establishing the SOSA Approach -- 11.5 A Successful Example of the SOSA Approach -- 11.6 Other Examples of SOSA Switches -- 11.6.1 From Antidepressants to Fungicides -- 11.6.2 Inhibition of Angiogenesis by the Antifungal Drug Itraconazole -- 11.6.3 From H1-Histamine Antagonists to Antimalaria Agents -- 11.6.4 Carprofen Cyclooxygenase-2 Inhibitors Yielding Alzheimer g-Secretase Modulators -- 11.7 Discussion -- 11.7.1 Safety and Bioavailability -- 11.7.2 Patentability -- 11.7.3 Originality -- 11.7.4 Orphan Diseases -- 11.8 Computer-Assisted Design Using Pharmacophores -- 11.9 Conclusions -- References.

PART C SELECTED APPROACHES TO POLYPHARMACOLOGICAL DRUG DISCOVERY -- 12. Selective Multitargeted Drugs -- 12.1 Introduction -- 12.2 Lead Generation -- 12.2.1 Screening -- 12.2.2 Framework Combination -- 12.3 Lead Optimization -- 12.4 Case Studies -- 12.4.1 Schizophrenia -- 12.4.2 Depression -- 12.4.3 Alzheimer's and Parkinson's Diseases -- 12.4.4 Pain -- 12.5 Summary -- References -- 13. Computational Multitarget Drug Discovery -- 13.1 Introduction -- 13.2 The Pharmacological Hunt of Yesteryear -- 13.2.1 Ethnopharmacy -- 13.2.2 Protein Targets -- 13.2.3 Hitting the Target -- 13.2.3.1 Random Screens -- 13.2.3.2 Directed Exploration -- 13.2.4 Similar Active Substances for Rational Selection -- 13.2.5 Cycling between Random and Directed Searches -- 13.2.6 Screening in Current Pharma -- 13.3 Established Technological Advancements -- 13.3.1 The Exploitable Niche -- 13.3.2 Target Dissection for Inhibitor Design -- 13.3.3 Rational Design and Optimization -- 13.3.4 Multitarget Dosing -- 13.4 Computational Drug Discovery -- 13.4.1 Principles and Data Sources -- 13.4.2 Docking -- 13.4.2.1 Translation -- 13.4.2.2 Orientation -- 13.4.2.3 Bond Rotation -- 13.4.3 Scoring and Discriminatory Functions -- 13.4.4 Relative Affinity Ranking -- 13.4.5 Comparison of Docking Methods -- 13.4.6 Ligand Comparison -- 13.5 More Recent Technical Improvements -- 13.5.1 Automated Binding Site Identification -- 13.5.2 Docking with Protein Target Dynamics -- 13.5.3 Structure Modeling for Target Docking -- 13.5.4 Ligand-Target Networks -- 13.6 Emerging Concepts -- 13.6.1 Starting with Nature -- 13.6.2 Peptides and Their Derivatives -- 13.6.3 Off-Label Drug Use -- 13.6.4 Off-Target Effects -- 13.6.5 Affinity, Entropy, Enthalpy, and Optimization -- 13.6.6 False Hits -- 13.6.7 Finding Targets of Known Inhibition -- 13.6.8 Personalized Pharmacology -- 13.6.9 Open-Source Drug Discovery.

13.6.10 Multitarget Design -- 13.6.11 Multidisease Screens and Reversing the Disease-Drug Search -- 13.7 Summary -- References -- 14. Behavior-Based Screening as an Approach to Polypharmacological Ligands -- 14.1 The Challenges of CNS Drug Discovery -- 14.2 In Vivo High-Throughput Screening -- 14.3 Screening Libraries of Compounds -- 14.4 Relationship between Molecular Properties and In Vivo CNS Activity -- 14.5 Following Screening Hits in Secondary Assays -- 14.6 Potential Therapeutic Value of Dual-Adenosine Compounds -- 14.7 Summary -- References -- 15. Multicomponent Therapeutics -- 15.1 Introduction -- 15.2 Why Drug Synergies are Statistically More Context-Dependent -- 15.3 How a Synergistic Mechanism Can Lead to Therapeutic Selectivity -- 15.4 Discussion -- References -- PART D CASE STUDIES -- 16. Discovery of Sunitinib as a Multitarget Treatment of Cancer -- 16.1 A Brief Introduction to Tumor Angiogenesis -- 16.2 Discovery of Sunitinib from Drug Design to First Evidence of Clinical Activity -- 16.3 Pharmacology of Sunitinib -- 16.4 Safety of Sunitinib -- 16.5 Activity of Sunitinib -- 16.5.1 Gastrointestinal Stromal Tumors (GISTs) -- 16.5.2 Renal Cell Carcinoma (RCC) -- 16.5.3 Neuroendocrine Tumors -- 16.5.4 Hepatocellular Carcinoma (HCC) -- 16.6 Surrogate Imaging Techniques to Capture Vascular Changes -- 16.7 Surrogate Biomarkers -- 16.8 Conclusion -- References -- 17. Antipsychotics -- 17.1 Definition and Diagnosis of Schizophrenia -- 17.2 Etiology and Pathophysiology of Schizophrenia -- 17.2.1 Dopamine -- 17.2.2 Serotonin -- 17.2.3 Glutamate -- 17.2.4 GABA -- 17.2.5 Acetylcholine -- 17.2.6 PDE10A -- 17.2.7 Tachykinins -- 17.3 Epidemiology -- 17.4 Medical Practice and Treatment Options -- 17.5 Case Studies -- 17.5.1 Typical Neuroleptics: Chlorpromazine and Its Structural Congeneric Phenothiazines -- 17.5.2 Atypical Neuroleptics.

17.5.2.1 Clozapine.