Drug Target Selection and Validation (Computer-Aided Drug Discovery and Design, 1)

✍ Scribed by Marcus T. Scotti (editor), Carolina L. Bellera (editor)

• Publisher: Springer
• Year: 2022
• Tongue: English
• Leaves: 266
• Category: Library

✦ Synopsis

The first book in the newly created book series, Computer-Aided Drug Discovery and Design, focuses on the computational aspects of early drug discovery, drug target identification, and validation. It revises current classical paradigms in target and phenotypic-based drug design with still ingrained approximations and concepts and discusses the research in the new network approach concept that include kinetic selectivity and metabolic analysis.
Many often-overlooked approximations and concepts in drug discovery are fully covered. Drug Target Selection and Validation includes both introductory sections and research-based sections to be of use to both students and research scientists in drug discovery, design, kinetics and metabolic analysis. Pharmaceutical scientists, pharmaceutics, drug developers, pharmacologists, biomedical researchers in computer science, medicinal chemists, and precision medicine developers benefit from the information provided. The book concludes with a chapter on chemical and structural databases.

✦ Table of Contents

Foreword
Acknowledgments
Contents
Contributors
Drug Discovery Paradigms: Target-Based Drug Discovery
1 Introduction
2 Target Identification
3 Binding Site Identification
Evolutionary Methods
Geometrical Methods
Energy-Based Methods
4 Target-Based Methodologies
Molecular Docking
Sampling Algorithms
Scoring Algorithms
Molecular Docking Limitations
Molecular Dynamics Simulations
Algorithms in Molecular Dynamics Simulations
Force Field in Molecular Dynamics Simulations
Limitations of Molecular Dynamics Simulations
De Novo Drug Design
Sampling, Scoring, and Optimization
Machine Learning in De Novo Drug Design
Limitations in De Novo Drug Design
5 Conclusions and Future Directions
References
Drug Discovery Paradigms: Phenotypic-Based Drug Discovery
1 Introduction
2 Advantages of Phenotypic Drug Discovery
3 Target Deconvolution
4 A New Paradigm: Network Pharmacology
5 High-Content Screening
6 Advanced 3D Cell Culture Platforms
7 Small Animal Models
8 Conclusions
References
Target Identification Approaches in Drug Discovery
1 Introduction
2 Approaches for Drug Target Identification
3 Direct or Affinity-Based Approaches
Target Identification by Photo Affinity Labeling
Target Identification by DARTS
Target Identification by Cellular Thermal SHIFT ASSay (CETSA)
4 Phenotype-Based Methods
Proteomics
Affinity-Based Protein Profiling (ABPPs)
SILAC
Isotope Coded Affinity Tag (ICAT)
ChemProteoBase
Morphology-Based Cell Assays
5 Genetic Approaches for Target Identification
CRISPR Cas System
6 Different CRISPR-Cas Systems and Their Applications
7 Conclusions
References
Introduction to Target Validation
1 Definition and Requirements of a Molecular Target
2 Experimental-Based Approaches
Forward Genetics
Reverse Genetics
Targeted Gene Replacement and Editing
Post-transcriptional Gene Silencing
Modulation of Protein Function
Chemical-Based Approaches
Forward Chemogenomics
Reverse Chemogenomics
Chemical Probes
3 Computational-Based Approaches
Predictive Chemogenomics
Molecular Network Technology
4 General Remarks and Prospective
References
Structure-Based Binding Pocket Detection and Druggability Assessment
1 Introduction
2 Binding Pocket Prediction
3 Druggability Prediction
4 Additional Challenges: Hidden/Cryptic Binding Sites
5 Final Remarks
References
Network-Based Target Identification
1 Introduction
2 Methodologies
Network-Based Inference Methods
NBI
Substructure-Drug-Target NBI (SDTNBI)
Balanced SDTNBI (bSDTNBI)
Similarity-Based Inference Methods
Random Walk-Based Methods
Local Community-Based Methods
Path-Based Methods
3 Web Servers
NetInfer
DASPfind
4 Applications
Discovery of New Targets for Known Compounds
Studies on GPCRs
Studies on Nuclear Receptors
Elucidation of the Molecular Mechanisms of Therapeutic Effects
Studies on Approved Drugs
Studies on Natural Products
Elucidation of the Molecular Mechanisms of Adverse Effects
5 Advantages and Limitations
References
The Current State of Precision Medicine and Targeted-Cancer Therapies: Where Are We?
1 Introduction
2 Precision (and Personalized) Medicine
3 Precision Medicine: How It All Began
4 The Precision Medicine Process and Integration into Cancer Treatment
5 How Precise Is Precision Medicine?
6 Advent of Targeted Cancer Therapy
7 Increasing the Precision of Cancer Therapeutics with Targeted Therapies
8 Tumor-Agnostic-Targeted Therapies
9 The Limitations and Challenges Associated with Targeted Therapies
10 Precision Medicine and the Future of Clinical Trials
11 Omics Technologies for Precision Medicine
12 Molecular Profiling and Biomarkers in Precision Medicine
13 More Than Mutations: Cancer Research Needs a Better Map
14 The Role of Companion Diagnostics in Precision and Personalized Medicine
15 Conclusions and Future Perspectives
References
Metabolic Control Analysis for Drug Target Selection Against Human Diseases
1 Introduction
2 Basic Principles of Metabolic Control Analysis
Control Coefficients
Summation Theorem
Flux Control Coefficient Estimation
Relationship Between Flux and Enzyme Activity
Experimental Determination of the Control Coefficient
Enzyme Titration with Inhibitors
In Vitro Pathway Reconstitution
Manipulation of Enzyme Expression in Cells
3 Elasticity Coefficients
Estimation of the Elasticity Coefficient from the Rate Equation
Estimation of the Elasticity Coefficient from the Substrate Saturation Curves
Experimental Determination of the Elasticity Coefficient Within Cells
Relationship Between Elasticity Coefficient and Flux Control Coefficient
Connectivity Theorem
4 Kinetic Modeling for CJai Determination
5 Conclusion
References
Progress on Open Chemoinformatic Tools for Drug Discovery
1 Introduction
2 Compound Databases
Databases to Support COVID-19 Research and Drug Discovery
Compound Databases of General Interest
3 Virtual Screening
Applications to COVID-19 Drug Discovery
4 Natural Products
Natural Product-Likeness
5 On the Rational Use of Free Resources
General Recommendations for the Proper Use of Open Source and Other Resources
6 Conclusions and Future Directions
References
Index