Title Computer aided drug design (CADD) : from ligand-based methods to structure-based approaches / edited by Mithun Rudrapal, Chukwuebuka Egbuna

Published San Diego : Elsevier, 2022 ©2022

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Description 1 online resource (324 pages) Series Drug Discovery Update Drug Discovery Update Contents Intro -- Computer Aided Drug Design (CADD): From Ligand-Based Methods to Structure-Based Approaches -- Copyright -- Contents -- Contributors -- Chapter 1: Introduction to drug design and discovery -- Chapter outline -- 1. Definition and concept of drug design and discovery -- 2. Historical perspectives of drug discovery -- 3. Process, strategies, and stages of drug discovery and development -- 3.1. Discovery phase -- 3.2. Preclinical phase -- 3.3. Clinical phase -- 3.4. Approval and postapproval phases -- 4. Traditional and modern approaches to drug discovery and development -- 4.1. Virtual screening -- 4.2. High-throughput screening -- 4.3. Phenotypic screening -- 4.4. Structure-based drug design -- 4.5. Fragment-based drug design -- 4.6. Ligand-based drug design -- 5. Rational drug design (RDD) and CADD -- 5.1. Structure-based drug design (SBDD) -- 5.1.1. Molecular docking -- 5.1.2. Molecular dynamics -- 5.2. Ligand-based drug design (LBDD) -- 5.2.1. Quantitative structure-activity relationship (QSAR) -- 5.2.2. Pharmacophore modeling and similarity search -- 5.2.3. Absorption, distribution, metabolism, excretion, and toxicity (ADMET) prediction -- 6. Conclusion -- References -- Chapter 2: Fundamental considerations in drug design -- Chapter outline -- 1. Fundamentals of rational drug design (RDD) -- 1.1. Rational drug design -- 1.2. Structure-based drug design (SBDD) -- 1.3. Ligand-based drug design (LBDD) -- 2. Concepts of physicochemical properties -- 2.1. Structural properties and stereochemistry -- 2.2. Drug receptors and receptor theories -- 2.2.1. Occupation theory -- 2.2.2. Rate theory -- 2.2.3. Induced fit theory -- 2.3. Pharmacokinetics and pharmacodynamics -- 2.4. SARs and QSARs -- 2.5. Prodrugs and drug metabolism -- 2.6. Metabolite antagonism and enzyme inhibition -- 2.7. Nucleic acid-based drug design -- 2.8. Lead compounds 2.9. Peptidomimetics and analog design -- 2.10. Reverse pharmacology and drug repurposing strategies -- 3. Fundamentals of computer-aided drug design (CADD) -- 3.1. Structure-based drug design (SBDD) -- 3.1.1. Docking -- 3.1.2. Molecular dynamics (MD) -- 3.1.3. Structure-based pharmacophore modeling -- 3.2. Ligand-based drug design (LBDD) -- 3.2.1. Similarity search -- 3.2.2. QSAR modeling -- 3.2.3. Ligand-based pharmacophore modeling -- 3.3. Virtual screening techniques -- 3.3.1. Structure- or target-based virtual screening -- 3.3.2. Successful applications of virtual screening -- 3.4. ADME analysis and measures of drug-likeness -- 4. Conclusion -- References -- Chapter 3: Ligand-based drug design (LBDD) -- Chapter outline -- 1. Introduction -- 2. Random and nonrandom screening -- 2.1. Drug metabolism studies -- 2.2. Serendipity method -- 2.3. Clinical observations -- 3. Drug discovery process -- 3.1. Ligand-based drug design (LBDD) -- 3.2. Structure-based drug design (SBDD) -- 4. Combinatorial chemistry -- 4.1. Unbiased library -- 4.2. Biased library -- 4.2.1. Solid-phase synthesis -- 4.2.2. Solution-phase synthesis -- 5. Lead modifications and optimization approaches -- 5.1. Pharmacophore -- 5.2. Structure-activity relationships (SARs) -- 6. Stereochemistry of drug molecules -- 6.1. Importance in drug action -- 6.2. Stereoselectivity in drug-receptor interaction -- 6.3. Stereospecific aspects in drug design -- 6.4. Stereochemistry in biological processes -- 6.5. Significance of stereoselectivity -- 7. Bioisosterism -- 7.1. Need and use of bioisosteric replacements -- 7.2. Classification of bioisosterism11-14 -- 7.2.1. Classical bioisosteres -- Monovalent bioisosteres -- Divalent bioisosteres -- Trivalent atoms or groups -- Tetrasubstituted atoms -- Ring equivalents -- 7.2.2. Nonclassical bioisosteres -- 8. Drug metabolism2,16,17 -- 8.1. Objectives 8.2. Prodrugs18 -- 8.2.1. Objectives -- 8.2.2. Classifications of prodrugs -- Based on the type of carrier moiety -- Carrier-linked prodrugs -- Bioprecursor prodrugs -- Based on cellular site of bioactivation -- Type I -- Type II -- 8.2.3. Essential functionalities associated with prodrugs scheming -- 8.3. Retrometabolism-based drug design (RMDD) -- 8.3.1. Principle -- 8.3.2. Soft drug design -- 8.3.3. Chemical delivery system -- 9. Virtual high-throughput screening (vHTS) -- 9.1. Tools for virtual high-throughput screening (vHTS) -- 9.1.1. Octopus -- 9.1.2. PyRx -- 9.1.3. Raccoon2 -- 9.2. Techniques for virtual high-throughput screening (vHTS) -- 9.2.1. Ligand-based vHTS -- 9.2.2. Structure-based vHTS -- 9.3. Lipinskis rule -- 9.4. Veber rule -- 9.5. ADMET screening -- 9.6. Toxicity prediction -- 9.7. Docking-based virtual screening (DBVS) -- 9.8. Pharmacophore-based virtual screening (PBVS) -- 9.8.1. Water thermodynamics -- 9.8.2. Binding free energy calculations -- Binding kinetics -- Binding site accessibility and drug size -- Conformational fluctuations -- Electrostatics -- Hydrophobicity and water -- Residence time -- Optimizing residence time -- 10. Conclusion -- Acknowledgment -- References -- Chapter 4: Quantitative structure-activity relationships (QSARs) -- Chapter outline -- 1. QSAR: Fundamentals and historical background -- 1.1. Definition -- 1.2. Historical background -- 2. Hammett equation -- 3. Hansch-Fujita model -- 4. Free and Wilson method -- 5. Protocols for managing a QSAR study -- 6. Conditions for the validity of the model -- 6.1. Regarding the variable selection -- 6.2. Regarding the variable validation -- 6.3. Regarding the model validation -- 6.4. Regarding the amount of variables -- 6.5. Regarding the biological validation -- 6.6. Regarding model recycling -- 7. 3D-QSAR -- 7.1. CoMFA -- 7.2. CoMSIA -- 7.3. SOMFA 7.4. GRID/GOLPE -- 7.5. HASL -- 7.6. COMPASS -- 8. Case study -- 9. Conclusion -- References -- Chapter 5: Fundamentals of molecular modeling in drug design -- Chapter outline -- 1. Fundamentals of computational chemistry -- 2. Basic concepts of quantum mechanics -- 3. Sketch approach, conversion of 2D structures in 3D form, and generation of 3D coordinates -- 4. Molecular dynamics simulation and its components -- 4.1. Force fields -- 4.2. Geometry optimization -- 4.3. Energy minimization -- 4.4. Conformational search -- 4.5. Genetic algorithms -- 4.6. Monte Carlo simulation -- 4.7. Artificial intelligence methods -- 4.8. Pharmacophore identification and molecular modeling -- 5. Molecular recognition in drug design -- 6. Thermodynamic consideration of drug designing -- 6.1. Methods of thermodynamic measurement for bimolecular interactions -- 6.1.1. Direct method -- 6.1.2. Indirect method by Vant Hoff analysis -- 6.2. Physical basis of intermolecular interaction -- 6.2.1. Total energy of intermolecular interactions -- 6.2.2. Estimating individual group components in ligand receptor interactions and cooperativity and thumb rules -- 7. Conclusion and future scope -- References -- Chapter 6: Pharmacophore modeling in drug design -- Chapter outline -- 1. Introduction -- 2. Computer-aided drug design -- 3. Pharmacophore concept -- 3.1. Ligand-based pharmacophore -- 3.2. Structure-based pharmacophore (SBP) -- 4. Pharmacophore model-based virtual screening (VS) -- 5. Pharmacophore elements and representation -- 6. Generation of pharmacophore models from receptor-ligand complex -- 7. Applications of pharmacophores in ADME-Tox -- 7.1. Pharmacophore-guided drug target identification -- 7.2. Multitargets by pharmacophore -- 7.3. Possible applications of multitarget ligands -- 7.3.1. Drug resistance -- 7.3.2. Prospective drug repositioning -- 8. Conclusion Bibliography References -- Chapter 7: Structure-based drug design (SBDD) -- Chapter outline -- 1. Computer-aided drug design -- 2. Structure-based drug design (SBDD) -- 2.1. Overview of the processes involved in structure-based drug design (SBDD)39 -- 2.2. Examples of SBDD -- 2.3. Case study of SBDD -- 3. Molecular docking -- 3.1. Various models pertaining to molecular docking -- 3.2. Classification of molecular docking systems -- 3.3. Docking based screening -- 3.4. Molecular docking steps and procedure/docking protocol -- 4. Molecular dynamics -- 4.1. Applications of MD -- 4.2. Binding free energy calculations with MMGBSA/PBSA -- 4.3. Molecular dynamics simulation using DESMOND -- 4.4. Case study -- 5. Conclusion -- References -- Chapter 8: Recent advances in CADD -- Chapter outline -- 1. Introduction -- 2. Role of informatics in drug discovery -- 2.1. Chemoinformatics in drug discovery -- 2.1.1. Database generation -- 2.1.2. Chemical descriptors -- 2.1.3. Role of informatics in drug development -- Identification of problem (disease) -- Target validation -- Identification and optimization of lead -- Preclinical and clinical trials -- Approval and commercialization -- 2.1.4. Role of omics in drug discovery -- Genomics -- Transcriptomics -- Proteomics -- Metabolomics -- 3. Databases used in drug discovery -- 3.1. Recent trends of ADMET -- 3.2. Prediction of physicochemical properties -- 3.2.1. Solubility -- 3.2.2. Ionization constant -- 3.2.3. Lipophilicity -- 3.3. Prediction of ADMET properties -- 3.3.1. Absorption -- 3.3.2. Distribution -- 3.3.3. Metabolism -- 3.3.4. Excretion -- 3.3.5. Toxicity -- 4. Fragment-based drug design -- 4.1. Library design for FBDD -- 4.2. Strategies in fragment-based drug design -- 4.2.1. Fragment growing -- 4.2.2. Fragment linking -- 4.2.3. Fragment merging -- 4.3. General consideration on fragment-based drug design Notes 5. Receptor-based de novo design Description based on publisher supplied metadata and other sources Subject Drugs -- Design -- Computer simulation Drugs -- Design -- Data processing Drugs -- Design -- Computer simulation Drugs -- Design -- Data processing Form Electronic book Author Rudrapal, Mithun Egbuna, Chukwuebuka ISBN 9780323914338 0323914330

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