| Description |
1 online resource (xxiii, 510 pages) : illustrations |
| Contents |
880-01 Frontmatter -- Color Plates -- Introduction: The Case for Polypharmacology / Andrew L Hopkins -- Polypharmacology: A Safety Concern in Drug Discovery. The Relevance of Off-Target Polypharmacology / Bruce D Car -- Screening for Safety-Relevant Off-Target Activities / Laszlo Urban, Steven Whitebread, Jacques Hamon, Dmitri Mikhailov, Kamal Azzaoui -- Pharmacological Promiscuity and Molecular Properties / Jens-Uwe Peters -- Kinases as Antitargets in Genotoxicity / Stephan Kirchner -- Activity at Cardiovascular Ion Channels: A Key Issue for Drug Discovery / Ian M Bell, Mark T Bilodeau, Armando A Lagrutta -- Prediction of Side Effects Based on Fingerprint Profiling and Data Mining / Jacques Migeon -- Polypharmacology: An Opportunity for Drug Discovery. Polypharmacological Drugs: ₃Magic Shotguns₄ for Psychiatric Diseases / Wesley K Kroeze, Bryan L Roth -- Polypharmacological Kinase Inhibitors: New Hopes for Cancer Therapy / Annalisa Petrelli -- Polypharmacology as an Emerging Trend in Antibacterial Discovery / Lynn L Silver -- A ₃Magic Shotgun₄ Perspective on Anticonvulsant Mechanisms / Matt T Bianchi, Kathy Chuang -- Selective Optimization of Side Activities (SOSA): A Promising way for Drug Discovery / Thierry Langer, Camille-Georges Wermuth -- Selected Approaches to Polypharmacological Drug Discovery. Selective Multitargeted Drugs / Richard Morphy -- Computational Multitarget Drug Discovery / Jeremy A Horst, Adrian Laurenzi, Brady Bernard, Ram Samudrala -- Behavior-Based Screening as an Approach to Polypharmacological Ligands / Dani Brunner, Vadim Alexandrov, Barbara Caldarone, Taleen Hanania, David Lowe, Jeff Schneider, Jayaraman Chandrasekhar -- Multicomponent Therapeutics / Alexis A Borisy, Grant R Zimmermann, Joseph Leh̀r -- Case Studies. Discovery of Sunitinib as a Multitarget Treatment of Cancer / Catherine Delbaldo, Camelia Colichi, Marie-Paule Sablin, Chantal Dreyer, Bertrand Billemont, Sandrine Faivre, Eric Raymond -- Antipsychotics / Claus Riemer -- Triple-Uptake Inhibitors (Broad-Spectrum Antidepressants) / Phil Skolnick -- Therapeutic Potential of Small Molecules Modulating the Cyclooxygenase₆5-Lipoxygenase Pathway / Wolfgang Albrecht, Stefan Laufer -- Drug Research Leading to Imatinib and beyond to Nilotinib / Paul W Manley, Jorg Zimmermann -- Towards Antimalarial Hybrid Drugs / Bernard Meunier -- Multitargeted Drugs for Treatment of Alzheimer's Disease / Andrea Cavalli, Maria Laura Bolognesi -- Carbonic Anhydrases: Off Targets, Add-On Activities, or Emerging Novel Targets? / Claudiu T Supuran -- Index |
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880-01/(S Machine generated contents note: pt. A POLYPHARMACOLOGY: A SAFETY CONCERN IN DRUG DISCOVERY -- 1. Relevance of Off-Target Polypharmacology / Bruce D. Car -- 2. Screening for Safety-Relevant Off-Target Activities / Kamal Azzaoui -- 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 / Jens-Uwe Peters -- 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 / Stephan Kirchner -- 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 / Armando A. Lagrutta -- 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 / Jacques Migeon -- 6.1. Introduction to BioPrint -- 6.1.1. Compounds -- 6.1.2. Assays -- 6.2. 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 -- pt. B POLYPHARMACOLOGY: AN OPPORTUNITY FOR DRUG DISCOVERY -- 7. Polypharmacological Drugs: "Magic Shotguns" for Psychiatric Diseases / Bryan L. Roth -- 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 / Annalisa Petrelli -- 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. 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 / Lynn L Silver -- 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. β-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. 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. "Magic Shotgun" Perspective on Anticonvulsant Mechanisms / Kathy Chuang -- 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 / Camille-Georges Wermuth -- 11.1. Introduction -- 11.2. Definition and Principle -- 11.3. Rationale of SOSA -- 11.4. Establishing the SOSA Approach -- 11.5. 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 Hl-Histamine Antagonists to Antimalaria Agents -- 11.6.4. Carprofen Cyclooxygenase-2 Inhibitors Yielding Alzheimer γ-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 -- pt. C SELECTED APPROACHES TO POLYPHARMACOLOGICAL DRUG DISCOVERY -- 12. Selective Multitargeted Drugs / Richard Morphy -- 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 / Ram Samudrala -- 13.1. Introduction -- 13.2. 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. 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 / Jayaraman Chandrasekhar -- 14.1. 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 / Joseph Lehar -- 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 -- pt. D CASE STUDIES -- 16. Discovery of Sunitinib as a Multitarget Treatment of Cancer / Eric Raymond -- 16.1. 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 Ceil 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 / Claus Riemer |
| Summary |
"Covers the two-sided nature of polypharmacology--its contribution to adverse drug reactions and its benefit in certain therapeutic drug classes. Addresses the important topic of polypharmacology in drug discovery, a subject that has not been thoroughly covered outside of scattered journal articles. Overviews state-of-the-art approaches and developments to help readers understand concepts and issues related to polypharmacology."-- Provided by publisher |
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"An essential outline of the main facets of polypharmacology in drug discovery research. Extending drug discovery opportunities beyond the "one drug, one target" philosophy, a polypharmacological approach to the treatment of complex diseases is emerging as a hot topic in both industry and academic research. Polypharmacology in Drug Discovery presents an overview of the various facets of polypharmacology and how it can be applied as an innovative concept for developing medicines for treating bacterial infections, epilepsy, cancer, psychiatric disorders, and more."-- Provided by publisher |
| Bibliography |
Includes bibliographical references and index |
| Notes |
English |
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Print version record |
| Subject |
Drug development.
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Drugs -- Toxicology.
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Pharmacology.
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Drugs -- Side effects.
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Drug Discovery
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Drug-Related Side Effects and Adverse Reactions
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Pharmaceutical Preparations -- chemistry
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Pharmacology
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pharmacology.
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MEDICAL -- Drug Guides.
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MEDICAL -- Nursing -- Pharmacology.
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MEDICAL -- Pharmacology.
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MEDICAL -- Pharmacy.
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Drugs -- Side effects
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Drug development
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Drugs -- Toxicology
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Pharmacology
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| Form |
Electronic book
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| Author |
Peters, Jens-Uwe.
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| LC no. |
2011052324 |
| ISBN |
9781118098141 |
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1118098145 |
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9781118098127 |
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1118098129 |
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9781280589324 |
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1280589329 |
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9781118098134 |
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1118098137 |
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9786613619150 |
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6613619159 |
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