In Silico Drug Design : Repurposing Techniques and Methodologies

__In Silico Drug Design: Repurposing Techniques and Methodologies__ explores the application of computational tools that can be utilized for this approach. The book covers theoretical background and methodologies of chem-bioinformatic techniques and network modeling and discusses the various applied strategies to systematically retrieve, integrate and analyze datasets from diverse sources. Other topics include __in silico__ drug design methods, computational workflows for drug repurposing, and network-based __in silico__ screening for drug efficacy. With contributions from experts in the field and the inclusion of practical case studies, this book gives scientists, researchers and R&D professionals in the pharmaceutical industry valuable insights into drug design. Front Matter Copyright Dedication Contributors About the Editor Preface Drug Repositioning: New Opportunities for Older Drugs Introduction The Fundamentals for Drug Repositioning Different Approaches to the Development of New Indications for Old Drugs Serendipity and Text Mining Observation of Unexpected Side Effects Detection of a New Role for the Existing Targets Identification of New Drug-Target Interactions Drug Repositioning for Specific Disease Phenotypes Conclusions Acknowledgment References Computational Drug Design Methods-Current and Future Perspectives Introduction Overview of Current Approaches Used in Computer-Aided Drug Design Classification of Computer-Aided Drug Design Methods Structure-Based Methods Ligand-Based Methods Hybrid Methods and Methods Based on End-Points Main Applications of Computer-Aided Drug Design Hit Finding Lead Optimization Case Studies: Successful Applications of Computer-Aided Drug Design Trending Concepts and Technologies Big Data Web Servers Workflows Machine Learning Applications of Machine Learning in Drug Discovery Deep Learning Artificial Intelligence Molecular Dynamics General Aspects of Molecular Dynamics Applications of Molecular Dynamics in Drug Discovery Challenges and Emerging Problems in Computer-Aided Drug Design Integration With Other Techniques Absorption, Distribution, Metabolism, and Excretion, and Toxicity Prediction Difficult and Emerging Targets Neglected Diseases Chemical Space Advance Multitarget Drug Discovery and Polypharmacology Training, Teaching, and Divulgation Conclusions Acknowledgments References Further Reading In Silico Drug Design Methods for Drug Repurposing Drug Repurposing Computational Approaches for Drug Repositioning Target-Based Methods Knowledge-Based Methods Signature-Based Methods Network-Based Methods Target Mechanism-Based Methods Examples of Successful Drug Repositioning Opportunities and Limitations of In Silico Drug Repositioning References Further Reading Computational Drug Repurposing for Neurodegenerative Diseases Neurodegenerative Diseases Drug Repurposing Activity-Based Drug Repurposing Phenotypic Screening Approach Target-Based Screening Computational Drug Repurposing Structure-Based Virtual Screening (Molecular Docking) Ligand-Based Methods Pharmacophore Model Method Quantitative Structure-Activity Relationship Methods Reverse Docking Methods Transcriptomic-Based Methods Genome-Wide Association Studies-Based Methods Network-Based Methods Integration of Methods Machine Learning-Based Approaches Literature-Based Discovery Methods Drug Repurposing Challenges Validation of Methods Drug Combination Discussion and Conclusion References Further Reading Repurposed Molecules: A New Hope in Tackling Neglected Infectious Diseases Introduction Part I: Current Knowledge and Challenges in Neglected Infectious Diseases Eukaryotic Neglected Infectious Diseases Leishmaniases Chagas Disease Human African Trypanosomiasis Human Taeniasis Echinococcoses Schistosomiasis Food-Borne Trematode Infections Lymphatic Filariasis Onchocerciasis Soil-Transmitted Helminthiasis Dracunculiasis Bacterial NIDs Buruli Ulcer Leprosy (Hansen's Disease) Trachoma Yaws Viral Diseases Dengue Chikungunya Rabies PART II: Tools and Strategies Useful Databases for Drug Repurposing in Neglected Infectious Diseases Computational Tools For Drug Repurposing in Neglected Infectious Diseases: A Virtual Translational Reality From Comp ... Ligand-Based Approaches Target-Based Approaches Integration of Databases and Computational Tools for Drug Repurposing in Neglected Infectious Diseases Perspectives and Concluding Remarks Acknowledgments References Further Reading Molecular Docking: A Structure-Based Approach for Drug Repurposing Introduction Molecular Docking Basic Requirements for Molecular Docking Structural Data Ligand Representation Receptor Representation Role of Water in Docking Studies Types of Docking Methodology Types of Interactions Approaches of Molecular Docking Shape Complementarity Approach Simulation Approach Mechanism of Docking Search Algorithms Scoring Functions Force Field-Based Scoring Function Empirical-Based Scoring Function Knowledge-Based Scoring Function Target-Specific Scoring Function Estimating Binding Affinity With Scoring Functions Exploring the Energy Landscape in Docking Protein Flexibility and Binding Affinity Prediction Postdocking Analysis Applications of Molecular Docking Limitations of Molecular Docking Available Software for Docking Drug Repurposing Types of Drug Repurposing Blind Search or Screening Method Target-Based Method Knowledge-Based Methods Signature-Based Methods Network- or Pathway-Based Method Targeted Mechanism-Based Method Case Studies Repurposing of Antipsychotic Drugs for Alzheimer's Disease Repurposed Drug of G-Protein Coupled Receptor Inhibitor Repurposed Drugs as Modulators of Protein-Protein Interactions Repurposed Drug as a Nuclear Receptor Antagonist Repurposed Drug as a Stabilizer of G-Quadruplex DNA Success of Private-Public Partnership for Drug Repurposing Limitations of Drug Repurposing Intellectual Property Considerations Conclusion References Further Reading Data Science Driven Drug Repurposing for Metabolic Disorders Introduction Overview of Metabolic Disorders Metabolism Metabolic Disorders and Metabolic Syndrome Different Components Underlying Metabolic Syndrome Classification of Metabolic Disorders General Classification Disorders in Protein Metabolism Due to the Inability to Metabolize Some Amino Acids Due to Organic Acid Disorders Due to the Urea Cycle Defect Which Is Caused by Any Defect in or Absence of an Enzyme or Cofactors in the Urea Cycle Disorders in Lipid Metabolism Disorders in Carbohydrate Metabolism Diabetes Mellitus Disorders in Hormone Metabolism Lysosomal Storage Disorders Mitochondrial Storage Disorders Pathophysiological Classification Metabolic Disorders That Give Rise to Intoxication Phenylketonuria Metabolic Disorders Involving Energy Metabolism Hypoglycemia Metabolic Disorder Involving Complex Molecules Lysosomal Storage Disorders Computational Approaches Next Generation Sequencing Personalized Medicine Big-Data Approaches Diabetic Retinopathy Screening Using Artificial Intelligence Drug Repurposing Based on -Omics-Data Mining Molecular Property Diagnostic Suite Genetics and -Omics Toolkit to Analyse Gene Function Functional Annotation of the Human Genome Classification of Common Human Diseases Immune Metabolic Interactions Metabolic System and Immune System Leptin IL-6 TNF-α Dietary Restriction in Metabolic Health Different Molecular Mechanisms Associated With Metabolic Disorders Epigenetics, Genetics and Transcriptomics Host Epigenetic Response in Immune-Metabolic Interactions Role of Genetics and Transcriptomics in Metabolic Disorders Structural Bioinformatics Mutation and Single Nucleotide Polymorphism-Based Structural Analysis Variation Databases Deleterious Mutation Prediction Role of Structural Bioinformatics in Single Nucleotide Polymorphisms Analysis Protein Secondary Structure Prediction Molecular Docking and Virtual Screening Molecular Dynamics Simulation Importance of Modeling, Informatics, Simulation, and Data Analytics in Drug Discovery Drug Repurposing Different Methods for Drug Repurposing Repurposed Drugs for Metabolic Disorders Outlook References Data-Driven Systems Level Approaches for Drug Repurposing: Combating Drug Resistance in Priority Pathogens Introduction High-Throughput Data-Driven Drug Repurposing Platforms Genomics-Based Approaches for Drug Repurposing Network-Based Approaches for Drug Repurposing Structural Proteomics-Based Approaches for Drug Repurposing Exploring Extended Target Space Pathogen Specific Essential Genes Capturing Genetic Complexity in Resistant Strains: Pan Genome Approach Drug-Resistance Mechanisms to Drive Drug-Repurposing Strategies Network-Based Target Exploration Biological Big Data and Network Analyses for Target Identification Protein-Protein Interaction Networks for Identifying Novel Drug Targets Metabolic Networks for Drug Target Prediction Gene Regulatory Networks for Identifying Novel Drug Targets Extended Chemical Space Conclusion References In Silico Repurposing of Cell Cycle Modulators for Cancer Treatment Targeting the Cell Cycle in the Treatment of Cancer Drug Repurposing in Cancer Drug Discovery In Silico Cell Cycle Modulator Repurposing Ligand-Based Drug Repurposing Target-Based Drug Repurposing Expression-Based Drug Repurposing Phenotype-Based Drug Repurposing Challenges and Future Direction Conclusion Acknowledgments References Proteochemometric Modeling for Drug Repositioning Overview of Drug Discovery Polypharmacology and Drug Repositioning Computational Drug Discovery Biological and Chemical Repositories Computational Drug Discovery Approaches Extending QSAR to Simultaneously Consider Biology and Chemistry via PCM Case Studies on the Use of PCM for Drug Repositioning Conclusion Acknowledgments References Drug Repurposing From Transcriptome Data: Methods and Applications Introduction Methods Similarity-Based Methods Gene Set Enrichment Analysis Co-Expressed Gene-Set Enrichment Analysis Other Metrics Machine-Learning Algorithms Network-Based Approaches Matrix Factorization Models Supervised Classifiers Applications Drug-Disease Connections Disease-Disease Similarities Drug-Drug Connections Drug-Target Connections Drug-Drug Combinations Databases and Tools NCBI GEO ArrayExpress LINCS DSigDB PharmGKB DrugMatrix CTD CDA CMap Clue MANTRA MarQ NFFinder Cogena ksRepo GOpredict Integrity Gene2Drug GeneExpressionSignature DvD DeSigN PDOD Conclusions References Omics-Driven Knowledge-Based Discovery of Anthelmintic Targets and Drugs Background: Parasitic Worms and Anthelmintics Used to Treat Them Omics Knowledge Expansion to Facilitate New Target/Drug Discovery Genomes Transcriptomes Proteomes Metabolomes Species-Centric, -Omics-Based, Drug-Target Identification Pan-Phylum, -Omics-Based, Drug-Target Identification Chemogenomic Screening for Identification of Drug-Like Compounds Experimental Screening, Confirmation, and Validation Future Considerations References Further Reading Analysis of Chemical Spaces: Implications for Drug Repurposing Introduction Available Chemical Data Network-Based Representations Chemical Space Networks for Drugs Chemical Space Networks for Bioactive Compounds Dimensionality Reduction Methods Principal Component Analysis Self-Organizing Maps Generative Topographic Mapping Learned Latent Representations of Chemical Space Scaffold-Based Representation Privileged Fragments Approach Hierarchical Clustering Approach Scaffold-Based Exploration of the Chemical Space Conclusion Acknowledgments References Examples and Case Studies Drug Repurposing in Search of Anti-Infectives: Need of the Hour in the Multidrug Resistance&s Introduction Computational Drug Repurposing Methods: A Brief Overview Drug Repurposing for Antibacterial Indication Infections Caused by Gram-Positive Bacteria Infections Caused by Gram-Negative Bacteria Infections Caused by Mycobacterium tuberculosis Drug Repurposing for Antiviral Indication Drug Repurposing for Neglected Tropical Diseases Current Treatments and Drug Development for Neglected Tropical Diseases Drug Repurposing for Antifungal Indication References Further Reading Application of In Silico Drug Repurposing in Infectious Diseases Introduction Why Is Drug Purposing Needed? No Drug Is Ever Understood Completely Why This Field of Drug Discovery Is Encouraging: Financial Benefits Rational Drug Design Pipeline and the Challenges Arise Who Is the Beneficiary Neglected Tropical Diseases Rare or Orphan Diseases Cancer Infectious Diseases Emerging Disease Like Zika Virus Identifying Repurposing Opportunities: Methods High-Throughput Screening Based Approach Computational Approach Knowledge Mining Clinical Indications Novel Target Target-Based Screening Challenges of Selectivity by In Silico Chemoinformatics-Based Methods Structure-Based and Simulation Genomics and Proteomics Driven Target Identification (Only for Repurposing) Genetic Analysis Methods Drug-Target and Disease-Drug Network/Association Web-Based Analysis Tools Machine Learning and Artificial Intelligence Other Challenges Like Sharing Information and Risk Summary and Future References In Silico Modeling of FDA-Approved Drugs for Discovery of Anticandida Agents: A Drug-Repurposing Approach Introduction Methodology Dataset Chem-Bioinformatics Approach to Identify Potential Drug-Target Associations in C. albicans Sequence Analyses Structural Analyses Augmenting Chemical Space within the Domain of Approved Drugs Proof of Concept Results and Discussion Identification of Potential Repurposable Drugs Identification of Potential Drug Targets in Candida albicans Case Study 1: Cetrimonium-A Potential Repurposable Drug Candidate Against MTS1 Case Study 2: Fusidic Acid-A Potential Repurposable Drug Candidate Against MEF1 and MEF2 Case Study 3: Nitrofural-A Potential Repurposable Drug Candidate Against Multiple Metabolic Enzymes in C. albicans Other Shortlisted Cases Aminoglycosidic Antibiotics-Potential Repurposable Anti-Candida Agents Mupirocin-A Potential Repurposable Anti-Candida Agent Gatifloxacin-A Potential Repurposable Anti-Candida Agent Tetracycline Analogues-Potential Repurposable Anti-Candida Agents Conclusion Acknowledgments References In Silico Modeling of FDA-Approved Drugs for Discovery of Anticancer Agents: A Drug-Repurposing Approach Introduction Examples of Structure-Based Virtual Ligand Screening of FDA-Approved Drugs for Discovery of Anticancer Agents Reprogramming Energy Metabolism Inducing Angiogenesis Evading Growth Suppressors Sustaining Proliferative Signaling Resisting Cell Death An Enabling Characteristic: Tumor-Promoting Inflammation Conclusion References Tackling Lung Cancer Drug Resistance Using Integrated Drug-Repurposing Strategy Introduction: Historical Perspective, Targets and Therapies of Lung Cancer Emergence, Cause and Statistics Lung Cancer Targets ErbB/HER Family of Proteins Anaplastic Lymphoma Kinase Mesenchymal Epithelial Transition Factor BRAF KRAS Rearranged During Transfection ROS1 Fibroblast Growth Factor Receptors Discoidin Domain Receptor 2 Phosphatidyl 3-Kinase Vascular Endothelial Growth Factor Therapies for Lung Cancer Drug Resistance Pattern in Lung Cancer Drug Resistance Towards Chemotherapy Drug Transporters Drug Inactivation DNA-Repair Pathways Loss of Intracellular Death Mechanisms Drug Resistance Towards Small Molecule Inhibitors Primary Resistance Acquired Resistance Resources for Drug Repurposing in Lung Cancer Drug Repositioning: A Case Study With HER Proteins of NSCLC Materials and Methods Results and Discussion Central Nervous System Activity and Human Oral Absorption Analysis Molecular Docking MCS and PASS Analysis Protein-Ligand Interaction Analysis Conclusion Acknowledgments References Further Reading In Silico Modeling of FDA-Approved Drugs for Discovery of Anti-Cancer Agents: A Drug-Repurposing Approach Introduction Basic In Silico Repurposing Strategy Workflow Big Data Collection and Integration Different Algorithms for Drug Repurposing Scientific Literature Mining Strategy Case Studies Transcriptional Signatures-Based Predictions for Anticancer Drug Repurposing Case Studies Network-Based Drug Repurposing for Anti-Cancer Drug Discovery Case Studies Ligand-Based Approach to Drug Repurposing for Anti-Cancer Drug Discovery Case Studies Structure-Based Approaches in Drug Repurposing Case Studies Multiple In Silico Strategy-Based Approach Case Studies Validation Techniques for In Silico Repurposing Study Summary and Future Prospectives Acknowledgments References Drug Repurposing by Connectivity Mapping and Structural Modeling Introduction Genomic C-MAPPING of the Bisphosphonate Gene Signature In Vitro Validation of C-MAP Hits Computational Modeling of Bisphosphonate-EGFR Interactions In Vitro Confirmation of Anticancer Effects Implications of In Silico Drug Repurposing Acknowledgments References In Silico Modeling of FDA-Approved Drugs for Discovery of Therapies Against Neglected Diseases: A Drug Repurposing Approach Introduction Cheminformatics and NTD-Oriented Drug Repurposing Virtual Screening The Similarity Ensemble Approach Molecular Topology and Promiscuity Determinants as Predictors of Drug Repurposing Bioinformatics and NTD-Oriented Drug Repurposing High-Throughput Literature Analysis Network Analysis Conclusion Acknowledgments References Ascorbic Acid Is a Potential Inhibitor of Collagenases-In Silico and In Vitro Biological Studies Introduction Drug Repositioning Molecular Modeling in Drug Discovery Molecular Docking Evaluation of Docking Results Matrix Metalloproteinases Inhibitors of MMPs Zinc-Binding Groups of MMP Inhibitors Experimental Procedures Molecular Docking Ligand Preparation Ligand Docking Molecular Dynamic Simulations Rheumatoid Synovial Fibroblast Culture for MMP-8 Conditioned Medium Fluorogenic MMP Activity Measurements MMP-8 Enzyme Assay Collagen Zymography Statistical Analyses Results Docking Studies Molecular Dynamic Simulations Simulation Analysis of 3DNG Protein With GM6001 Simulation Analysis of 3DNG Protein With Vitamin C Inhibition of MMP-8 Activity Against Collagen by Ascorbic Acid Discussion Acknowledgments References Bioinformatic Approaches for Repurposing and Repositioning Antibiotics, Antiprotozoals, and Antivirals Introduction DRR Framework Genomics and DRR Identify Essential Genes/Metabolic Pathways in Pathogens for DRR Identify Alternative Pathways to Achieve an Essential Function for Effective DRR Genomic Analysis to Reduce Drug Resistance and Environmental Impact Transcriptomics and DRR: A Word of Caution Structural Biology and DRR Phenotypic Screening, Big Data, and Deep Learning Conventional Phenotypic Screening in DRR Problems With Phenotypic Screening and Its Deep Learning Solution Acknowledgments References Further Reading In Silico Databases and Tools for Drug Repurposing Introduction Databases for Drug Repurposing ADReCS-Target BindingDB BioGRID ChEMBL ChemProt 3.0 Comparative Toxicogenomics Database CTD2 Dashboard DGIdb 3.0 DrugBank 5.0 DrugCentral ECOdrug IntAct KEGG Databases Pharos PDBBind PDID PharmGKB STITCH SuperDRUG2 SuperTarget IUPHAR/BPS Guide to Pharmacology Therapeutic Target Database ChemSpider ZINC 15 SWEETLEAD Side Effect Resource (SIDER) ClinicalTrials.gov DrugPath Connectivity Map ArrayExpress Gene Expression Omnibus PubChem DailyMed Encyclopedia of Rare Disease Annotation for Precision Medicine Orphanet repoDB Repurposed Drug Database FAERS Offsides ACToR WITHDRAWN Web-Based and Stand-Alone Tools for Drug Repurposing Cogena DIGEP-Pred Drug vs. Disease Galahad Gene2drug ksRepo MANTRA NFFinder Drug Repurposing Recommendation System DrugNet GeneDiseaseRepositioning Hetionet and Project Rephetio PDOD PROMISCUOUS ChemMine Tools C-SPADE ChemTreeMap DeSigN SuperPred BalestraWeb DASPFind DDI-CPI DINIES DPDR-CPI and DRAR-CPI DT-Web and DT-Hybrid HitPick iDrugTarget Polypharmacology Browser SEA SwissTargetPrediction DR. PRODIS DrugQuest MeSHDD PolySearch2 LimTox Drug Repurposing Hub RE:fine Drugs Conclusion Acknowledgments References An Overview of Computational Methods, Tools, Servers, and Databases for Drug Repurposing Drug Repurposing Phenotype-Based (Blinded) Screening Knowledge and Database Methods Target-Based Methods Signature-Based Methods Pathway or Network-Based Methods Computer-Aided Drug Design CADD Techniques Virtual Screening Docking-Based Virtual Screening Structure-Based Pharmacophore Screening Molecular Dynamics Simulation Target-Based Drug Repurposing Using CADD Techniques Drug/Small Molecule Databases Drug Target Databases Prediction of 3D Structure of Drug Targets Homology Modeling/Comparative Modeling Identification of Template Structure Alignment of Target Sequence to Template Model Building Model Optimization and Validation Binding Site Identification Virtual Screening for Drug Repurposing Drug Repurposing for Protein-Protein Interactions Databases and Tools for Drug Repurposing Using Gene Expression Signatures Drug Repurposing for Aurora Kinase C Target Using CADD (A Case Study) Aurora Kinases C Model Building and Validation Binding Site Identification and Virtual Screening of DrugBank Compounds Summary References In Silico Drug Repurposing for MDR Bacteria: Opportunities and Challenges Introduction Computational Methods and Drug Discovery National Microbial Pathogen Data Resource Functional Antibiotic Resistant Metagenomic Element Database (FARME-DB) MEGARes Database ARGs-OAP (Antibiotic Resistance Gene-Online Analysis Pipeline) NFFinder Database Connectivity Map Network-Based Drug Repurposing Adverse Drug Reactions and Drug Repurposing Comprehensive Antibiotic Resistance Database DeepARG Database Antibiotic Resistance Genes Database BacMet Antibiotic Resistance Gene-ANNOTation (ARG-ANNOT) Database for Multidrug Resistance Genes (DbMDR) Challenges for In Silico Drug Discovery Conclusion References Further Reading Drug Repositioning Strategies to Explore New Candidates Treating Prostate Cancer Introduction Evolution of Pharmacology and the Drug Discovery Process Drug Repositioning as a Promising Strategy in Drug Discovery Challenges in Drug Discovery for Prostate Cancer A Conceptual Summary of Drug Repositioning Approaches Publicly Available Web-Based Tools for Drug Repositioning Connectivity Map DeSigN BalestraWeb PROMISCUOUS STITCH RE:fine Drugs DSigDB DRUGSURV canSAR geneXpharma Web-Based Tools as a Reference for Drug Repositioning Studies RepurposeDB repoDB Repurposed Noncancer Drugs Via Web-Based Tools for Prostate Cancer Treatment Determination of Inputs as Prostate Cancer Signatures Queries Based on Genes Queries Based on Differentially Expressed Genes or Proteins Evaluation of the Outputs from Web-Based Tool Aiming at Drug Repositioning Future Directions and Concluding Remarks Acknowledgment References PDID: Database of Experimental and Putative Drug Targets in Human Proteome Introduction Development and Outline of the PDID Database eFindSite SMAP ILbind Predictive Quality of ILbind, eFindSite, and SMAP Content of the PDID Database Use of the PDID Database Summary Acknowledgment References Index A B C D E F G H I J K L M N O P Q R S T U V W Y Z In Silico Drug Design: Repurposing Techniques and Methodologies explores the application of computational tools that can be utilized for this approach. The book covers theoretical background and methodologies of chem-bioinformatic techniques and network modeling and discusses the various applied strategies to systematically retrieve, integrate and analyze datasets from diverse sources. Other topics include in silico drug design methods, computational workflows for drug repurposing, and network-based in silico screening for drug efficacy. With contributions from experts in the field and the inclusion of practical case studies, this book gives scientists, researchers and R&D professionals in the pharmaceutical industry valuable insights into drug design. Discusses the theoretical background and methodologies of useful techniques of cheminformatics and bioinformatics that can be applied for drug repurposing Offers case studies relating to the in silico modeling of FDA-approved drugs for the discovery of antifungal, anticancer, antiplatelet agents, and for drug therapies against diseases Covers tools and databases that can be utilized to facilitate in silico methods for drug repurposing