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Table of Contents
Cover
Title
Copyright
End User License Agreement
Contents
Preface
REFERENCES
List of Contributors
Ligand and Structure-Based Drug Design (LBDD and SBDD): Promising Approaches to Discover New Drugs
Igor José dos Santos Nascimento1,2,3,* and Ricardo Olimpio de Moura3
INTRODUCTION
DRUG DESIGN AND DISCOVERY: PAST AND TODAY METHODS AND OTHER APPROACHES
Natural Compounds (NC)
Synthetic Drugs: Classical Approaches
Bioisosterism
Molecular Simplification
Molecular Hybridization
Combinatorial Chemistry
High Throughput Screening (HTS)
Target-Based Drug Discovery (TBDD)
Phenotypic-Based Drug Discovery (PBDD)
Multitarget Drug Design (MDD)
Computer-Aided Drug Design (CADD)
SBDD AND LBDD METHODS IN DRUG DESIGN
Structure-Based Drug Design (SBDD)
Homology Modeling
Molecular Docking and Molecular Dynamics Simulations
Fragment-Based Drug Design (FBDD) or de novo Drug Design
Density Function Theory (DFT)
Ligand-Based Drug Design (LBDD)
Quantitative Structure-Activity Relationship (QSAR)
Pharmacophore Modeling
Machine and Deep Learning and Artificial Methods
CHALLENGES AND OPPORTUNITIES IN LBDD AND SBDD APPROACHES TO DESIGN AND DISCOVER NEW DRUGS
CONCLUSION
ACKNOWLEDGMENTS
REFERENCES
Quantitative Structure-activity Relationship (QSAR) in Studying the Biologically Active Molecules
Serap ÇETINKAYA1, Burak TÜZÜN2,* and Emin SARIPINAR3
INTRODUCTION
QSAR's Use
QSAR Model Development
2D-QSAR Analysis
Fragment-Based 2D-QSAR Methods
3D-QSAR
4D-QSAR
5D- and 6D-QSARs
Molecular Modelling and QSAR
Importance of the Validation of QSAR Models
Means of Proof for QSAR Models
Internal Validation
External Validation
Easily Reproducible QSAR Protocol
CONCLUSION
REFERENCES.
Pharmacophore Mapping: An Important Tool in Modern Drug Design and Discovery
Dharmraj V. Pathak1, Abha Vyas1, Sneha R. Sagar1, Hardik G. Bhatt2 and Paresh K. Patel1,*
INTRODUCTION
Definitions of Pharmacophore
Pharmacophore: History
Pharmacophoric Features
LIGAND BASED PHARMACOPHORE
Ligand-Based Pharmacophore Modeling
Selection of the Right Set of Compounds and their Initial Structure
Conformational Search
Feature Representation and Extraction
Pattern Identification/Molecular Alignment
Scoring the Common Pharmacophore
Pharmacophore Tools and their Algorithms
Pharmacophore Validation
Cost Analysis
Fisher's Randomization Test
Test Set Prediction
Leave-one-out Method
3D-QSAR
Pharmacophore Based 3D QSAR
STRUCTURE BASED PHARMACOPHORE
Structure Based Pharmacophore Model Generation
Active Site Identification
Complementary Image Construction
Query Generation, Searching and Hit Analysis
Validation
Virtual Screening
Prefiltering
APPLICATION OF PHARMACOPHORE MAPPING
A Successful Example of Pharmacophore-based Drug Design: An Example of How Anthranilamide Derivatives Were Successfully Shown to be Promising Factor Xa Inhibitors [163]
Applications of Artificial Intelligence in Pharmacophore Mapping
Limitations of Pharmacophore Modeling
CONCLUSION
ACKNOWLEDGEMENTS
REFERENCES
Up-to-Date Developments in Homology Modeling
Muhammed Tilahun Muhammed1,* and Esin Aki-Yalcin2
INTRODUCTION
BRIEF HISTORY OF HOMOLOGY MODELING
HOMOLOGY MODELING PROCEDURE
Identification and Selection of templates
Sequence Alignments and Alignment Correction
Model Building
Loop Modeling
Side-Chain Modeling
Model Optimization
Model Evaluation and Validation
OVERVIEW OF HOMOLOGY MODELING TOOLS
MODELLER
I-TASSER
SWISS-MODEL
Prime
Phyre2.
HHPRED
RosettaCM
Alpha Fold
CASE STUDY
APPLICATIONS OF HOMOLOGY MODELING IN DRUG DISCOVERY
CONCLUSION
REFERENCES
Anticancer Activity of Medicinal Plants Extract and Molecular Docking Studies
Serap ÇETINKAYA1 and Burak TÜZÜN2,*
INTRODUCTION
Computer Aided Drug Design (CADD)
Ligand-based Approach
Structure (Receptor)-based Approach
Covalent Interactions in Biological Systems
Molecular Docking: Non-Covalent and Covalent Docking
Docking Methods in Software
Fixed Docking
Flexible-Fixed Docking
Flexible Docking
Types of Docking Calculations Algorithms
Stepwise Structure Algorithm
Monte Carlo Sampling Algorithm
Genetic Algorithm
Lamarckian Genetic Algorithm
Biplane Space Sampling
Shape Matching Algorithm
Molecular Docking Software
Artemisia sieversiana
Rosmarinus officinalis
Allium sativum
Zingiber officinale
CONCLUSION
REFERENCES
FBDD &
De Novo Drug Design
Anwesha Das1,†, Arijit Nandi2,†, Vijeta Kumari3 and Mallika Alvala4,*
INTRODUCTION
TYPES OF DRUG DESIGN
Structure or Receptor-based Drug Design (SBDD)
Ligand-based Drug Design (LBDD)
Sampling Methods in De novo Drug Design (DNDD)
EVOLUTIONARY ALGORITHMS IN DNDD
ARTIFICIAL INTELLIGENCE (AI) IN DNDD
DEEP REINFORCEMENT LEARNING (DRL) IN DNDD
Recurrent Neural Networks (RNN)
Convolutional Neural Network (CNN)
Generative Adversarial Network (GAN)
Autoencoder (AE)
Variational Autoencoder (VAE)
Sequence-to-Sequence Autoencoder (seq2seq AE)
Adversarial Autoencoder (AAE)
PARTICLE SWARM OPTIMIZATION (PSO) FOR DNDD
PARAMETERS OF EVALUATION
Diversity and Novelty
Desired Properties
Synthetic Feasibility
BRIDGING TOXICOGENOMICS AND MOLECULAR DESIGN
DNDD FOR COVID-19
BUILDING COMMUNITY AND REGULATORY ACCEPTANCE OF DL-METHOD FOR DNDD
FBDD.
Fragment Libraries
Fragment Expansion Strategy
Fragment Optimization Strategy
Fragment Growing
Fragment Linking
Fragment Merging
In silico Strategies for Fragment-to-ligand Optimization
Hotspot Analysis and Pocket Druggability Prediction
SAR Catalogue
Molecular Docking
Machine Learning and Deep Learning
DNDD
Novel Molecules Generating Software for The Binding Pocket of Protein's Binding Site
Pharmacokinetic Property Prediction of The Novel Compounds
Prediction of Synthesizability with The Novel Compounds
Synthesizability-aware Methods
Case Studies
PROTAC AND MOLECULAR GLUE
CONCLUSION
REFERENCES
Molecular Simulation in Drug Design: An Overview of Molecular Dynamics Methods
Fernando D. Prieto-Martínez1,*, Yelzyn Galván-Ciprés2 and Blanca Colín-Lozano3
INTRODUCTION
Historical Background
THEORETICAL INTERLUDE
The Basics: Generating Equations of Motion
Breaking Molecular Interactions Down to Physical Contributions: Enter Molecular Force Field
A Primer on Thermodynamics and Statistical Mechanics
THE OVERARCHING PROBLEM: SAMPLING
CURRENT LIMITATIONS OF MOLECULAR DYNAMICS
MOLECULAR DYNAMICS PRACTICE AT A GLANCE
Prior to Simulation
First Steps
Commonly Used Force Fields
Available Software
Desmond
GROMACS
NAMD
OpenMM
YASARA
Building the System
Running a MD Simulation
Simulation Analysis
RALTEGRAVIR: A CASE STUDY
A Look into the HIV-1 Integrase
The Drug Discovery Process
The Development of Raltegravir
WORKING EXAMPLE: MOLECULAR DYNAMICS TUTORIAL USING DESMOND
Generalities
Making an Atomistic Simulation of Crambin
Setting Up the System
Building the Simulation Box
Reparametrization Using the AMBER99SB-ILDN Force Field
Initializing the Simulation Protocol: Minimization
Equilibration and Dynamics.
Trajectory Analysis
Analysis with MDTraj
CONCLUSION
ACKNOWLEDGEMENTS
REFERENCES
Quantum Chemistry in Drug Design: Density Function Theory (DFT) and Other Quantum Mechanics (QM)-related Approaches
Samuel Baraque de Freitas Rodrigues1, Rodrigo Santos Aquino de Araújo2, Thayane Regine Dantas de Mendonça3, Francisco Jaime Bezerra Mendonça-Júnior2, Peng Zhan4 and Edeildo Ferreira da Silva-Júnior1,3,*
INTRODUCTION TO THE HISTORY OF QUANTUM CHEMISTRY (QC)
HOHENBERG-KOHN-SHAM THEOREM - DENSITY FUNCTIONAL THEORY (DFT)
Hohenberg-Kohn Existence Theorem
Hohenberg-Kohn Variational Theorem
Kohn-Sham Self-Consistent Field Methodology
CHEMICAL REACTIVITY INDEXES BY DENSITY FUNCTIONAL THEORY (DFT)
Chemical Potential and Electronegativity
Fukui Functions
DENSITY FUNCTIONAL THEORY (DFT)-RELATED APPROACHES
Hybrid Method: Quantum Mechanics / Molecular Mechanics (QM/MM)
DFT CALCULATIONS IN DRUG DESIGN &
DEVELOPMENT
Drug-Target Interactions
GABAA Receptor Inhibition
Understand Enzymatic Mechanisms of Catalysis
Cytidine Deaminase
RNA-dependent RNA Polymerase (RdRp) in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
Oxidized Polyvinyl Alcohol Hydrolase (OPH) from Pseudomonas O-3 Strain
Polyethylene Terephthalate Hydrolase (PETase) from Ideonella Sakaiensis
Exploring Catalytic Reactions of Cysteine Protease (Papain-like Proteins)
Papain Protease
Falcipain-2 from Plasmodium Falciparum
Cruzain Protease from Trypanosoma cruzi, and Rhodesain from T. brucei
Main Protease (Mpro or 3CLpro) from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
METALLOPROTEASES
Iron(III)-Catalyzed Aerobic Degradation by Biphenyl 2,3-dioxygenase (BphA)
Mushroom Copper-Containing Tyrosinase
[NiFe] Hydrogenase from Desulfovibrio Gigas.
QUANTUM CHEMICAL (QC) METHODS AND THEIR USES FOR DESIGNING DRUGS - VIEWPOINT AND COMPUTER REQUIRE- MENTS.
Title
Copyright
End User License Agreement
Contents
Preface
REFERENCES
List of Contributors
Ligand and Structure-Based Drug Design (LBDD and SBDD): Promising Approaches to Discover New Drugs
Igor José dos Santos Nascimento1,2,3,* and Ricardo Olimpio de Moura3
INTRODUCTION
DRUG DESIGN AND DISCOVERY: PAST AND TODAY METHODS AND OTHER APPROACHES
Natural Compounds (NC)
Synthetic Drugs: Classical Approaches
Bioisosterism
Molecular Simplification
Molecular Hybridization
Combinatorial Chemistry
High Throughput Screening (HTS)
Target-Based Drug Discovery (TBDD)
Phenotypic-Based Drug Discovery (PBDD)
Multitarget Drug Design (MDD)
Computer-Aided Drug Design (CADD)
SBDD AND LBDD METHODS IN DRUG DESIGN
Structure-Based Drug Design (SBDD)
Homology Modeling
Molecular Docking and Molecular Dynamics Simulations
Fragment-Based Drug Design (FBDD) or de novo Drug Design
Density Function Theory (DFT)
Ligand-Based Drug Design (LBDD)
Quantitative Structure-Activity Relationship (QSAR)
Pharmacophore Modeling
Machine and Deep Learning and Artificial Methods
CHALLENGES AND OPPORTUNITIES IN LBDD AND SBDD APPROACHES TO DESIGN AND DISCOVER NEW DRUGS
CONCLUSION
ACKNOWLEDGMENTS
REFERENCES
Quantitative Structure-activity Relationship (QSAR) in Studying the Biologically Active Molecules
Serap ÇETINKAYA1, Burak TÜZÜN2,* and Emin SARIPINAR3
INTRODUCTION
QSAR's Use
QSAR Model Development
2D-QSAR Analysis
Fragment-Based 2D-QSAR Methods
3D-QSAR
4D-QSAR
5D- and 6D-QSARs
Molecular Modelling and QSAR
Importance of the Validation of QSAR Models
Means of Proof for QSAR Models
Internal Validation
External Validation
Easily Reproducible QSAR Protocol
CONCLUSION
REFERENCES.
Pharmacophore Mapping: An Important Tool in Modern Drug Design and Discovery
Dharmraj V. Pathak1, Abha Vyas1, Sneha R. Sagar1, Hardik G. Bhatt2 and Paresh K. Patel1,*
INTRODUCTION
Definitions of Pharmacophore
Pharmacophore: History
Pharmacophoric Features
LIGAND BASED PHARMACOPHORE
Ligand-Based Pharmacophore Modeling
Selection of the Right Set of Compounds and their Initial Structure
Conformational Search
Feature Representation and Extraction
Pattern Identification/Molecular Alignment
Scoring the Common Pharmacophore
Pharmacophore Tools and their Algorithms
Pharmacophore Validation
Cost Analysis
Fisher's Randomization Test
Test Set Prediction
Leave-one-out Method
3D-QSAR
Pharmacophore Based 3D QSAR
STRUCTURE BASED PHARMACOPHORE
Structure Based Pharmacophore Model Generation
Active Site Identification
Complementary Image Construction
Query Generation, Searching and Hit Analysis
Validation
Virtual Screening
Prefiltering
APPLICATION OF PHARMACOPHORE MAPPING
A Successful Example of Pharmacophore-based Drug Design: An Example of How Anthranilamide Derivatives Were Successfully Shown to be Promising Factor Xa Inhibitors [163]
Applications of Artificial Intelligence in Pharmacophore Mapping
Limitations of Pharmacophore Modeling
CONCLUSION
ACKNOWLEDGEMENTS
REFERENCES
Up-to-Date Developments in Homology Modeling
Muhammed Tilahun Muhammed1,* and Esin Aki-Yalcin2
INTRODUCTION
BRIEF HISTORY OF HOMOLOGY MODELING
HOMOLOGY MODELING PROCEDURE
Identification and Selection of templates
Sequence Alignments and Alignment Correction
Model Building
Loop Modeling
Side-Chain Modeling
Model Optimization
Model Evaluation and Validation
OVERVIEW OF HOMOLOGY MODELING TOOLS
MODELLER
I-TASSER
SWISS-MODEL
Prime
Phyre2.
HHPRED
RosettaCM
Alpha Fold
CASE STUDY
APPLICATIONS OF HOMOLOGY MODELING IN DRUG DISCOVERY
CONCLUSION
REFERENCES
Anticancer Activity of Medicinal Plants Extract and Molecular Docking Studies
Serap ÇETINKAYA1 and Burak TÜZÜN2,*
INTRODUCTION
Computer Aided Drug Design (CADD)
Ligand-based Approach
Structure (Receptor)-based Approach
Covalent Interactions in Biological Systems
Molecular Docking: Non-Covalent and Covalent Docking
Docking Methods in Software
Fixed Docking
Flexible-Fixed Docking
Flexible Docking
Types of Docking Calculations Algorithms
Stepwise Structure Algorithm
Monte Carlo Sampling Algorithm
Genetic Algorithm
Lamarckian Genetic Algorithm
Biplane Space Sampling
Shape Matching Algorithm
Molecular Docking Software
Artemisia sieversiana
Rosmarinus officinalis
Allium sativum
Zingiber officinale
CONCLUSION
REFERENCES
FBDD &
De Novo Drug Design
Anwesha Das1,†, Arijit Nandi2,†, Vijeta Kumari3 and Mallika Alvala4,*
INTRODUCTION
TYPES OF DRUG DESIGN
Structure or Receptor-based Drug Design (SBDD)
Ligand-based Drug Design (LBDD)
Sampling Methods in De novo Drug Design (DNDD)
EVOLUTIONARY ALGORITHMS IN DNDD
ARTIFICIAL INTELLIGENCE (AI) IN DNDD
DEEP REINFORCEMENT LEARNING (DRL) IN DNDD
Recurrent Neural Networks (RNN)
Convolutional Neural Network (CNN)
Generative Adversarial Network (GAN)
Autoencoder (AE)
Variational Autoencoder (VAE)
Sequence-to-Sequence Autoencoder (seq2seq AE)
Adversarial Autoencoder (AAE)
PARTICLE SWARM OPTIMIZATION (PSO) FOR DNDD
PARAMETERS OF EVALUATION
Diversity and Novelty
Desired Properties
Synthetic Feasibility
BRIDGING TOXICOGENOMICS AND MOLECULAR DESIGN
DNDD FOR COVID-19
BUILDING COMMUNITY AND REGULATORY ACCEPTANCE OF DL-METHOD FOR DNDD
FBDD.
Fragment Libraries
Fragment Expansion Strategy
Fragment Optimization Strategy
Fragment Growing
Fragment Linking
Fragment Merging
In silico Strategies for Fragment-to-ligand Optimization
Hotspot Analysis and Pocket Druggability Prediction
SAR Catalogue
Molecular Docking
Machine Learning and Deep Learning
DNDD
Novel Molecules Generating Software for The Binding Pocket of Protein's Binding Site
Pharmacokinetic Property Prediction of The Novel Compounds
Prediction of Synthesizability with The Novel Compounds
Synthesizability-aware Methods
Case Studies
PROTAC AND MOLECULAR GLUE
CONCLUSION
REFERENCES
Molecular Simulation in Drug Design: An Overview of Molecular Dynamics Methods
Fernando D. Prieto-Martínez1,*, Yelzyn Galván-Ciprés2 and Blanca Colín-Lozano3
INTRODUCTION
Historical Background
THEORETICAL INTERLUDE
The Basics: Generating Equations of Motion
Breaking Molecular Interactions Down to Physical Contributions: Enter Molecular Force Field
A Primer on Thermodynamics and Statistical Mechanics
THE OVERARCHING PROBLEM: SAMPLING
CURRENT LIMITATIONS OF MOLECULAR DYNAMICS
MOLECULAR DYNAMICS PRACTICE AT A GLANCE
Prior to Simulation
First Steps
Commonly Used Force Fields
Available Software
Desmond
GROMACS
NAMD
OpenMM
YASARA
Building the System
Running a MD Simulation
Simulation Analysis
RALTEGRAVIR: A CASE STUDY
A Look into the HIV-1 Integrase
The Drug Discovery Process
The Development of Raltegravir
WORKING EXAMPLE: MOLECULAR DYNAMICS TUTORIAL USING DESMOND
Generalities
Making an Atomistic Simulation of Crambin
Setting Up the System
Building the Simulation Box
Reparametrization Using the AMBER99SB-ILDN Force Field
Initializing the Simulation Protocol: Minimization
Equilibration and Dynamics.
Trajectory Analysis
Analysis with MDTraj
CONCLUSION
ACKNOWLEDGEMENTS
REFERENCES
Quantum Chemistry in Drug Design: Density Function Theory (DFT) and Other Quantum Mechanics (QM)-related Approaches
Samuel Baraque de Freitas Rodrigues1, Rodrigo Santos Aquino de Araújo2, Thayane Regine Dantas de Mendonça3, Francisco Jaime Bezerra Mendonça-Júnior2, Peng Zhan4 and Edeildo Ferreira da Silva-Júnior1,3,*
INTRODUCTION TO THE HISTORY OF QUANTUM CHEMISTRY (QC)
HOHENBERG-KOHN-SHAM THEOREM - DENSITY FUNCTIONAL THEORY (DFT)
Hohenberg-Kohn Existence Theorem
Hohenberg-Kohn Variational Theorem
Kohn-Sham Self-Consistent Field Methodology
CHEMICAL REACTIVITY INDEXES BY DENSITY FUNCTIONAL THEORY (DFT)
Chemical Potential and Electronegativity
Fukui Functions
DENSITY FUNCTIONAL THEORY (DFT)-RELATED APPROACHES
Hybrid Method: Quantum Mechanics / Molecular Mechanics (QM/MM)
DFT CALCULATIONS IN DRUG DESIGN &
DEVELOPMENT
Drug-Target Interactions
GABAA Receptor Inhibition
Understand Enzymatic Mechanisms of Catalysis
Cytidine Deaminase
RNA-dependent RNA Polymerase (RdRp) in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
Oxidized Polyvinyl Alcohol Hydrolase (OPH) from Pseudomonas O-3 Strain
Polyethylene Terephthalate Hydrolase (PETase) from Ideonella Sakaiensis
Exploring Catalytic Reactions of Cysteine Protease (Papain-like Proteins)
Papain Protease
Falcipain-2 from Plasmodium Falciparum
Cruzain Protease from Trypanosoma cruzi, and Rhodesain from T. brucei
Main Protease (Mpro or 3CLpro) from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)
METALLOPROTEASES
Iron(III)-Catalyzed Aerobic Degradation by Biphenyl 2,3-dioxygenase (BphA)
Mushroom Copper-Containing Tyrosinase
[NiFe] Hydrogenase from Desulfovibrio Gigas.
QUANTUM CHEMICAL (QC) METHODS AND THEIR USES FOR DESIGNING DRUGS - VIEWPOINT AND COMPUTER REQUIRE- MENTS.