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Drug Selectivity : An Evolving Concept in Medicinal Chemistry.

By: Contributor(s): Material type: TextTextSeries: Methods and Principles in Medicinal Chemistry SeriesPublisher: Newark : John Wiley & Sons, Incorporated, 2018Copyright date: ©2018Edition: 1st edDescription: 1 online resource (538 pages)Content type:
  • text
Media type:
  • computer
Carrier type:
  • online resource
ISBN:
  • 9783527674411
Subject(s): Genre/Form: Additional physical formats: Print version:: Drug SelectivityDDC classification:
  • 615.19
LOC classification:
  • RM301 .D784 2018
Online resources:
Contents:
Cover -- Title Page -- Copyright -- Contents -- Preface -- A Personal Foreword -- Part I Introduction -- Chapter 1 Polypharmacology in Drug Discovery -- 1.1 Polypharmacology -- 1.2 Multitarget versus Target-Specific Drugs -- 1.2.1 "Master Key Compounds -- 1.2.2 Safety Panels -- 1.3 Polypharmacology and Related Concepts in Drug Discovery -- 1.3.1 Drug Repurposing -- 1.3.2 Combination of Drugs -- 1.3.3 In Vivo Testing -- 1.4 Polypharmacology (and Polypharmacy): Case Studies -- 1.4.1 Polypharmacology in Epigenetics -- 1.4.2 Charting the Epigenetic Relevant Chemical Space -- 1.4.3 Polypharmacy for the Treatment of HIV Infections -- 1.5 Computational Strategies to Explore Polypharmacology -- 1.5.1 Chemogenomics: Intersection of Chemical and Biological Spaces -- 1.5.2 Structure-Multiple Activity Relationships -- 1.5.3 Proteochemometric Modeling -- 1.5.4 Target Fishing -- 1.5.5 Data Mining of Side Effects and Interactions for Drug Repurposing -- 1.5.6 Systems Pharmacology -- 1.5.7 Polypharmacology Fingerprints -- 1.6 Summary Conclusions -- Acknowledgments -- References -- Part II Selectivity of Marketed Drugs -- Chapter 2 Kinase Inhibitors -- 2.1 Overview -- 2.2 Kinase Profiling -- 2.3 Definition and Quantification of Selectivity Levels -- 2.4 Selectivity of Approved Kinase Inhibitors -- 2.4.1 Non-covalent Type I and Type II SMKIs -- 2.4.2 Allosteric SMKIs -- 2.4.3 Lipid Kinase Inhibitor -- 2.4.4 Covalent Inhibitors -- 2.5 Conclusion and Perspective -- Acknowledgment -- References -- Chapter 3 Repositioning of Drug - New Indications for Marketed Drugs -- 3.1 Introduction -- 3.2 New Uses from Adverse Effects -- 3.2.1 Dapoxetine for Premature Ejaculation -- 3.2.2 Sildenafil for Erectile Dysfunction -- 3.3 New Uses Based on Known Mechanism of Action -- 3.3.1 Duloxetine for Stress Urinary Incontinence (SUI).
3.3.2 Thalidomide for Erythema Nodosum Leprosum (ENL) and Multiple Myeloma -- 3.4 New Uses from Genome, Network, and Signal Pathway Analysis -- 3.4.1 Identification of Sunitinib and Dasatinib for Breast Cancer Brain Metastasis -- 3.5 New Uses Based on New Target Identification (Off-Target Effects) -- 3.5.1 Antidepressant Drug, Amoxapine, for Alleviating Cancer Drug Toxicity of Irinotecan -- 3.6 Computational and Systematic Drug Repositioning -- 3.6.1 Methods Based on Knowledge of Side Effects -- 3.6.2 Methods Based on Transcriptomics Data (Transcriptional Profile) -- 3.6.3 Methods Based on Genome-Wide Association Study (GWAS) -- 3.6.4 Methods Based on Network and Pathways Analysis -- 3.6.5 Methods Based on Off-Target Effects -- 3.7 Perspective -- Acknowledgment -- References -- Chapter 4 Discovery Technologies for Drug Repurposing -- 4.1 Introduction -- 4.2 Biological Drug Screening Methods -- 4.2.1 Phenotypic Screening -- 4.2.1.1 Animal-Based Screening -- 4.2.1.2 Cell-Based Screening -- 4.2.2 Target-Based Screening -- 4.3 In silico Tools for Drug Repurposing -- 4.3.1 Docking -- 4.3.2 Chemoinformatics -- 4.3.3 Protein Binding Site -- 4.3.4 Combining Drug-Centric with Protein-Centric Approaches -- 4.3.5 Network Pharmacology -- 4.3.6 Mining of Big Data -- 4.4 Conclusion -- References -- Part III Unselective Drugs in Drug Discovery -- Chapter 5 Personalized Medicine -- 5.1 Roots of Personalized Medicine -- 5.2 The Return of the Active Pharmaceutical Ingredients (APIs) -- 5.3 Systems Pharmacology -- 5.4 The Patient in the Focus of Research -- 5.5 Personalized Therapy -- 5.6 Gene Therapy -- 5.7 Regenerative Medicine -- 5.8 Individualized Medicines -- 5.9 Stratified Medicines -- 5.10 Drug Selectivity -- 5.11 Smart Innovation -- 5.12 Electronic Health -- 5.13 Doctor and Patient -- 5.14 The Competent Patient -- 5.15 Conclusion -- References.
Chapter 6 Drug Discovery Strategies for the Generation of Multitarget Ligands against Neglected Tropical Diseases -- 6.1 Introduction -- 6.2 Drug Discovery for NTDs: The Past, the Present, and the Future -- 6.3 Search for New Anti-Trypanosomatid MTDL Hits: A Phenotypic Approach -- 6.4 Search for New Anti-Trypanosomatid MTDL Hits: A Target-Based Approach -- 6.5 Search for New Anti-Trypanosomatid MTDL Hits: A Drug Targeting Approach -- 6.6 Search for New Anti-Trypanosomatid MTDL Hits: A Combined Target/Targeting Approach -- 6.7 Conclusions -- References -- Chapter 7 Designing Approaches to Multitarget Drugs -- 7.1 Introduction -- 7.2 Target-Based Approaches for Multitarget Drug Design -- 7.2.1 Designing Approaches for Structurally Related Targets -- 7.2.1.1 Fragment-Based Approach -- 7.2.2 Designing Approaches for Structurally Unrelated Targets -- 7.2.2.1 Crystallography/SAR -- 7.2.2.2 Molecular Docking/Pharmacophore Matching -- 7.3 Ligand-Based Approaches for Multitarget Drug Design -- 7.3.1 Designing Approaches for Structurally Related Targets -- 7.3.1.1 Fragment-Based Approach -- 7.3.1.2 Machine Learning -- 7.3.1.3 SAR around a Lead -- 7.3.1.4 Pharmacophore-Based Approach -- 7.3.2 Designing-In Approaches for Structurally Unrelated Targets -- 7.3.2.1 Fragment-Based Approach -- 7.3.2.2 Pharmacophore-Based Approach -- 7.3.2.3 SAR around a Lead -- 7.3.2.4 Mining Literature Data -- 7.4 Designing Approaches Based on Phenotypic Assays -- 7.5 Conclusions -- References -- Chapter 8 The Linker Approach: Drug Conjugates -- 8.1 Introduction -- 8.1.1 Targeted Delivery -- 8.2 Drug Conjugates -- 8.2.1 Small Molecule Drug Conjugates -- 8.2.1.1 Chances and Challenges -- 8.2.1.2 Examples -- 8.2.2 Antibody-Drug Conjugates/Protein-Drug Conjugates -- 8.2.2.1 Chances and Challenges -- 8.2.2.2 Examples -- 8.2.3 Polymer-Drug Conjugates -- 8.2.3.1 Chances and Challenges.
8.2.3.2 Examples -- 8.3 Linker Chemistry -- 8.3.1 Demands on a Linker or How to Link Drugs -- 8.3.2 Linker Types -- 8.4 Conclusion and Future Perspective -- References -- Chapter 9 Merged Multiple Ligands -- 9.1 Introduction -- 9.2 Computational Methods Utilized in Designing MMLs -- 9.2.1 Bioactivity Data Sources -- 9.2.2 Utilizing Known Polypharmacology to Identify MMLs -- 9.2.3 Applying QSAR Models to Identifying and Optimizing MMLs -- 9.2.4 MMLs Developed Based on Fragments -- 9.2.5 Utilizing Protein Crystal Structures in Identifying MMLs -- 9.3 Examples of Medicinal Chemistry Efforts of Designing MMLs in Drug Discovery Projects -- 9.3.1 MMLs in Oncology -- 9.3.2 MML Targeting for Neurodegenerative Disease -- 9.3.2.1 MMLs for the Treatment of Alzheimer's Disease -- 9.3.2.2 MML for the Treatment of Parkinson's Disease -- 9.3.3 MML for the Treatment of Depression -- 9.3.4 MMLs for the Treatment of Cardiovascular Diseases -- 9.3.5 MML for the Treatment of Diabetes and Related Metabolic Diseases -- 9.3.6 MML for the Treatment of Inflammation and Pain -- 9.4 Conclusions and Future Outlook -- References -- Chapter 10 Pharmacophore Generation for Multiple Ligands -- 10.1 Introduction -- 10.2 Ligand-Based Pharmacophore Modeling -- 10.3 Structure-Based Pharmacophore Modeling -- 10.4 Pharmacophore-Based Virtual Screening -- 10.5 Pharmacophore-Based De Novo Design -- 10.6 Limitations for Pharmacophore Modeling -- 10.7 Practical Strategy for Pharmacophore-Based Discovery of Multiple Ligands -- 10.8 Linked Fluoroquinolone-Flavonoid Hybrids as Potent Antibiotics against Drug-Resistant Microorganisms -- 10.9 N-Phenylquinazolin-4-Amine Hybrids as Dual Inhibitors of VEGFR-2 and HDAC -- 10.10 Dual Inhibitors of Phospholipase A2 and Human Leukotriene A4 Hydrolase as Anti-Inflammatory Drugs.
10.11 Dual Antagonists of the Bradykinin B1 and B2 Receptors Based on a Postulated Common Pharmacophore from Existing Non-Peptide Antagonists -- 10.12 Dual-Acting Peptidomimetics with Opioid Agonist-Neurokinin-1 Antagonist Effect -- 10.13 Novel Dual-Acting Compounds Targeting the Adenosine A2A Receptor and Adenosine Transporter for Neuroprotection -- 10.14 Aminobenzimidazoles as Dual-Acting Butyrylcholinesterase Inhibitors and hCB2R Ligands to Combat Neurodegenerative Disorders -- 10.15 Dual Acetylcholinesterase Inhibitors-Histamine H3 Receptor Antagonists for Treating Alzheimer's Disease -- 10.16 Identification of Potential Dual Agonists of FXR and TGR5 Using E-Pharmacophore-Based Virtual Screening -- 10.17 Arylboronic Acids as Dual-Acting FAAH and TRPV1 Ligands -- 10.18 Dual Type II Inhibitors of TGF&amp -- rmbeta -- -Activated Kinase 1 (TAK1) and Mitogen-Activated Protein Kinase 2 (MAP4K2) -- 10.19 Conclusion and Outlook -- References -- Chapter 11 Cellular Assays -- 11.1 Introduction -- 11.2 Cell-Based Molecular Assays -- 11.2.1 Ligand Binding Assays -- 11.2.2 Chemoproteomic-Based Assays -- 11.2.3 Signaling Assays -- 11.2.4 Automated Patch Clamping -- 11.2.5 Protein-Protein Interaction Assays -- 11.2.6 Protein Trafficking Assays -- 11.2.7 Chemogenomic-Based Assays -- 11.3 Cell Phenotypic Assays -- 11.3.1 Reporter Gene Assays -- 11.3.2 High Content Imaging Assays -- 11.3.3 Label-Free Cell Phenotypic Assays -- 11.4 Summary -- 11.5 Current and Future Perspectives -- References -- Part IV Therapeutic Areas for Designed Multiple Ligands -- Chapter 12 Developing Serotonergic Antidepressants Acting on More Than the Serotonin Transporter -- 12.1 5-HT Transporter-Based Multiple Ligands for Depression -- 12.2 Beyond SSRIs: Strategies to Improve upon SSRI Antidepressant Activity.
12.3 Roster of Serotonergic Targets for Drug Developed Outside of the Serotonin Transporter (SERT).
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Cover -- Title Page -- Copyright -- Contents -- Preface -- A Personal Foreword -- Part I Introduction -- Chapter 1 Polypharmacology in Drug Discovery -- 1.1 Polypharmacology -- 1.2 Multitarget versus Target-Specific Drugs -- 1.2.1 "Master Key Compounds -- 1.2.2 Safety Panels -- 1.3 Polypharmacology and Related Concepts in Drug Discovery -- 1.3.1 Drug Repurposing -- 1.3.2 Combination of Drugs -- 1.3.3 In Vivo Testing -- 1.4 Polypharmacology (and Polypharmacy): Case Studies -- 1.4.1 Polypharmacology in Epigenetics -- 1.4.2 Charting the Epigenetic Relevant Chemical Space -- 1.4.3 Polypharmacy for the Treatment of HIV Infections -- 1.5 Computational Strategies to Explore Polypharmacology -- 1.5.1 Chemogenomics: Intersection of Chemical and Biological Spaces -- 1.5.2 Structure-Multiple Activity Relationships -- 1.5.3 Proteochemometric Modeling -- 1.5.4 Target Fishing -- 1.5.5 Data Mining of Side Effects and Interactions for Drug Repurposing -- 1.5.6 Systems Pharmacology -- 1.5.7 Polypharmacology Fingerprints -- 1.6 Summary Conclusions -- Acknowledgments -- References -- Part II Selectivity of Marketed Drugs -- Chapter 2 Kinase Inhibitors -- 2.1 Overview -- 2.2 Kinase Profiling -- 2.3 Definition and Quantification of Selectivity Levels -- 2.4 Selectivity of Approved Kinase Inhibitors -- 2.4.1 Non-covalent Type I and Type II SMKIs -- 2.4.2 Allosteric SMKIs -- 2.4.3 Lipid Kinase Inhibitor -- 2.4.4 Covalent Inhibitors -- 2.5 Conclusion and Perspective -- Acknowledgment -- References -- Chapter 3 Repositioning of Drug - New Indications for Marketed Drugs -- 3.1 Introduction -- 3.2 New Uses from Adverse Effects -- 3.2.1 Dapoxetine for Premature Ejaculation -- 3.2.2 Sildenafil for Erectile Dysfunction -- 3.3 New Uses Based on Known Mechanism of Action -- 3.3.1 Duloxetine for Stress Urinary Incontinence (SUI).

3.3.2 Thalidomide for Erythema Nodosum Leprosum (ENL) and Multiple Myeloma -- 3.4 New Uses from Genome, Network, and Signal Pathway Analysis -- 3.4.1 Identification of Sunitinib and Dasatinib for Breast Cancer Brain Metastasis -- 3.5 New Uses Based on New Target Identification (Off-Target Effects) -- 3.5.1 Antidepressant Drug, Amoxapine, for Alleviating Cancer Drug Toxicity of Irinotecan -- 3.6 Computational and Systematic Drug Repositioning -- 3.6.1 Methods Based on Knowledge of Side Effects -- 3.6.2 Methods Based on Transcriptomics Data (Transcriptional Profile) -- 3.6.3 Methods Based on Genome-Wide Association Study (GWAS) -- 3.6.4 Methods Based on Network and Pathways Analysis -- 3.6.5 Methods Based on Off-Target Effects -- 3.7 Perspective -- Acknowledgment -- References -- Chapter 4 Discovery Technologies for Drug Repurposing -- 4.1 Introduction -- 4.2 Biological Drug Screening Methods -- 4.2.1 Phenotypic Screening -- 4.2.1.1 Animal-Based Screening -- 4.2.1.2 Cell-Based Screening -- 4.2.2 Target-Based Screening -- 4.3 In silico Tools for Drug Repurposing -- 4.3.1 Docking -- 4.3.2 Chemoinformatics -- 4.3.3 Protein Binding Site -- 4.3.4 Combining Drug-Centric with Protein-Centric Approaches -- 4.3.5 Network Pharmacology -- 4.3.6 Mining of Big Data -- 4.4 Conclusion -- References -- Part III Unselective Drugs in Drug Discovery -- Chapter 5 Personalized Medicine -- 5.1 Roots of Personalized Medicine -- 5.2 The Return of the Active Pharmaceutical Ingredients (APIs) -- 5.3 Systems Pharmacology -- 5.4 The Patient in the Focus of Research -- 5.5 Personalized Therapy -- 5.6 Gene Therapy -- 5.7 Regenerative Medicine -- 5.8 Individualized Medicines -- 5.9 Stratified Medicines -- 5.10 Drug Selectivity -- 5.11 Smart Innovation -- 5.12 Electronic Health -- 5.13 Doctor and Patient -- 5.14 The Competent Patient -- 5.15 Conclusion -- References.

Chapter 6 Drug Discovery Strategies for the Generation of Multitarget Ligands against Neglected Tropical Diseases -- 6.1 Introduction -- 6.2 Drug Discovery for NTDs: The Past, the Present, and the Future -- 6.3 Search for New Anti-Trypanosomatid MTDL Hits: A Phenotypic Approach -- 6.4 Search for New Anti-Trypanosomatid MTDL Hits: A Target-Based Approach -- 6.5 Search for New Anti-Trypanosomatid MTDL Hits: A Drug Targeting Approach -- 6.6 Search for New Anti-Trypanosomatid MTDL Hits: A Combined Target/Targeting Approach -- 6.7 Conclusions -- References -- Chapter 7 Designing Approaches to Multitarget Drugs -- 7.1 Introduction -- 7.2 Target-Based Approaches for Multitarget Drug Design -- 7.2.1 Designing Approaches for Structurally Related Targets -- 7.2.1.1 Fragment-Based Approach -- 7.2.2 Designing Approaches for Structurally Unrelated Targets -- 7.2.2.1 Crystallography/SAR -- 7.2.2.2 Molecular Docking/Pharmacophore Matching -- 7.3 Ligand-Based Approaches for Multitarget Drug Design -- 7.3.1 Designing Approaches for Structurally Related Targets -- 7.3.1.1 Fragment-Based Approach -- 7.3.1.2 Machine Learning -- 7.3.1.3 SAR around a Lead -- 7.3.1.4 Pharmacophore-Based Approach -- 7.3.2 Designing-In Approaches for Structurally Unrelated Targets -- 7.3.2.1 Fragment-Based Approach -- 7.3.2.2 Pharmacophore-Based Approach -- 7.3.2.3 SAR around a Lead -- 7.3.2.4 Mining Literature Data -- 7.4 Designing Approaches Based on Phenotypic Assays -- 7.5 Conclusions -- References -- Chapter 8 The Linker Approach: Drug Conjugates -- 8.1 Introduction -- 8.1.1 Targeted Delivery -- 8.2 Drug Conjugates -- 8.2.1 Small Molecule Drug Conjugates -- 8.2.1.1 Chances and Challenges -- 8.2.1.2 Examples -- 8.2.2 Antibody-Drug Conjugates/Protein-Drug Conjugates -- 8.2.2.1 Chances and Challenges -- 8.2.2.2 Examples -- 8.2.3 Polymer-Drug Conjugates -- 8.2.3.1 Chances and Challenges.

8.2.3.2 Examples -- 8.3 Linker Chemistry -- 8.3.1 Demands on a Linker or How to Link Drugs -- 8.3.2 Linker Types -- 8.4 Conclusion and Future Perspective -- References -- Chapter 9 Merged Multiple Ligands -- 9.1 Introduction -- 9.2 Computational Methods Utilized in Designing MMLs -- 9.2.1 Bioactivity Data Sources -- 9.2.2 Utilizing Known Polypharmacology to Identify MMLs -- 9.2.3 Applying QSAR Models to Identifying and Optimizing MMLs -- 9.2.4 MMLs Developed Based on Fragments -- 9.2.5 Utilizing Protein Crystal Structures in Identifying MMLs -- 9.3 Examples of Medicinal Chemistry Efforts of Designing MMLs in Drug Discovery Projects -- 9.3.1 MMLs in Oncology -- 9.3.2 MML Targeting for Neurodegenerative Disease -- 9.3.2.1 MMLs for the Treatment of Alzheimer's Disease -- 9.3.2.2 MML for the Treatment of Parkinson's Disease -- 9.3.3 MML for the Treatment of Depression -- 9.3.4 MMLs for the Treatment of Cardiovascular Diseases -- 9.3.5 MML for the Treatment of Diabetes and Related Metabolic Diseases -- 9.3.6 MML for the Treatment of Inflammation and Pain -- 9.4 Conclusions and Future Outlook -- References -- Chapter 10 Pharmacophore Generation for Multiple Ligands -- 10.1 Introduction -- 10.2 Ligand-Based Pharmacophore Modeling -- 10.3 Structure-Based Pharmacophore Modeling -- 10.4 Pharmacophore-Based Virtual Screening -- 10.5 Pharmacophore-Based De Novo Design -- 10.6 Limitations for Pharmacophore Modeling -- 10.7 Practical Strategy for Pharmacophore-Based Discovery of Multiple Ligands -- 10.8 Linked Fluoroquinolone-Flavonoid Hybrids as Potent Antibiotics against Drug-Resistant Microorganisms -- 10.9 N-Phenylquinazolin-4-Amine Hybrids as Dual Inhibitors of VEGFR-2 and HDAC -- 10.10 Dual Inhibitors of Phospholipase A2 and Human Leukotriene A4 Hydrolase as Anti-Inflammatory Drugs.

10.11 Dual Antagonists of the Bradykinin B1 and B2 Receptors Based on a Postulated Common Pharmacophore from Existing Non-Peptide Antagonists -- 10.12 Dual-Acting Peptidomimetics with Opioid Agonist-Neurokinin-1 Antagonist Effect -- 10.13 Novel Dual-Acting Compounds Targeting the Adenosine A2A Receptor and Adenosine Transporter for Neuroprotection -- 10.14 Aminobenzimidazoles as Dual-Acting Butyrylcholinesterase Inhibitors and hCB2R Ligands to Combat Neurodegenerative Disorders -- 10.15 Dual Acetylcholinesterase Inhibitors-Histamine H3 Receptor Antagonists for Treating Alzheimer's Disease -- 10.16 Identification of Potential Dual Agonists of FXR and TGR5 Using E-Pharmacophore-Based Virtual Screening -- 10.17 Arylboronic Acids as Dual-Acting FAAH and TRPV1 Ligands -- 10.18 Dual Type II Inhibitors of TGF&amp -- rmbeta -- -Activated Kinase 1 (TAK1) and Mitogen-Activated Protein Kinase 2 (MAP4K2) -- 10.19 Conclusion and Outlook -- References -- Chapter 11 Cellular Assays -- 11.1 Introduction -- 11.2 Cell-Based Molecular Assays -- 11.2.1 Ligand Binding Assays -- 11.2.2 Chemoproteomic-Based Assays -- 11.2.3 Signaling Assays -- 11.2.4 Automated Patch Clamping -- 11.2.5 Protein-Protein Interaction Assays -- 11.2.6 Protein Trafficking Assays -- 11.2.7 Chemogenomic-Based Assays -- 11.3 Cell Phenotypic Assays -- 11.3.1 Reporter Gene Assays -- 11.3.2 High Content Imaging Assays -- 11.3.3 Label-Free Cell Phenotypic Assays -- 11.4 Summary -- 11.5 Current and Future Perspectives -- References -- Part IV Therapeutic Areas for Designed Multiple Ligands -- Chapter 12 Developing Serotonergic Antidepressants Acting on More Than the Serotonin Transporter -- 12.1 5-HT Transporter-Based Multiple Ligands for Depression -- 12.2 Beyond SSRIs: Strategies to Improve upon SSRI Antidepressant Activity.

12.3 Roster of Serotonergic Targets for Drug Developed Outside of the Serotonin Transporter (SERT).

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Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, 2024. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries.

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