Modeling Inhibitors of Matrix Metalloproteinases

Cover
Half Title
QSAR in Environmental and Health Sciences Series
Modeling Inhibitors of Matrix Metalloproteinases
Copyright
Dedication
Contents
Acknowledgment
Series Introduction
Preface
Editor Biography
List of Contributors
Part A. Fundamentals of Molecular Modeling
	1. 2D-QSAR Studies: Regression and Classification-Based QSAR Studies
		Contents
		Abstract
		1.1 Introduction
		1.2 Classification of Computer-Aided Drug Design
		1.3 Application of QSAR in the Early Stages of Drug Discovery
		1.4 Various Types of QSAR Studies
		1.5 Two-dimensional-QSAR Model Development
			1.5.1 Dataset Selection and Pre-Processing of Data
			1.5.2 Dataset Division (Training Set and Test Set)
			1.5.3 Calculating Molecular Descriptors
			1.5.4 Feature Selection Technique
			1.5.5 Two-Dimensional-QSAR Model Building
				1.5.5.1 Linear 2D-QSAR Models
				1.5.5.2 Non-Linear QSAR Models
				1.5.5.3 Validation Parameters for Non-Linear QSAR Study
			1.5.6 Interpretation and Applicability Domain Analysis
		1.6 Software, Database, and Web Services Available for QSAR Study
		1.7 Summary
		References
	2. 3D-QSAR Studies: CoMFA, CoMSIA, and Topomer CoMFA Methods
		Contents
		Abstract
		2.1 Introduction
		2.2 History/Origin of 3D-QSAR Study
		2.3 Comparative Molecular Field Analysis
			2.3.1 CoMFA Methodology
			2.3.2 Advantages and Disadvantages of CoMFA
			2.3.3 Factors Affecting the Performance and Outcome of CoMFA
				2.3.3.1 Diversity of Molecules and Molecular Alignment
				2.3.3.2 Biological Activity/Data of the Molecules
				2.3.3.3 3D Ligand-Structure Optimization
				2.3.3.4 Conformational Analysis of Molecules
				2.3.3.5 Biological Conformation Determination of Molecules
				2.3.3.6 Molecular Interaction Energy Field Calculation
		2.4 Comparative Molecular Similarity Indices Analysis
			2.4.1 The Methodology of CoMSIA
			2.4.2 The Advantages of CoMSIA
		2.5 Topomer CoMFA
			2.5.1 The Methodology of Topomer CoMFA
			2.5.2 The Advantages of Topomer CoMFA
		2.6 Summary
		References
	3. Other Modeling Approaches: Pharmacophore Mapping, Molecular Docking, and Molecular Dynamic Simulation Studies
		Contents
		Abstract
		3.1 Introduction
		3.2 Pharmacophore Mapping: An Overview
			3.2.1 Pharmacophore Model and Pharmacophore Fingerprint
			3.2.2 A Short Trip to the Pharmacophoric Features
				3.2.2.1 Automated Perception of Chemical Features
				3.2.2.2 Basic Interactions and Representation of Pharmacophoric Features
			3.2.3 Pharmacophore Elucidation
				3.2.3.1 Manually Created Pharmacophore Models
				3.2.3.2 Ligand-Based Pharmacophore Models
				3.2.3.3 Receptor-Based Pharmacophore Models
			3.2.4 Pharmacophore-Based Virtual Screening
		3.3 Molecular Docking Study
			3.3.1 Stages of Molecular Docking Study
				3.3.1.1 Sampling
				3.3.1.2 Scoring Functions
			3.3.2 Protein-Protein Docking
			3.3.3 Fragment-Based Docking
			3.3.4 Inverse Docking
			3.3.5 Nanoparticle Docking
		3.4 Molecular Dynamics Simulations
			3.4.1 Analysis of the Interface Dynamics
		3.5 Advance Approaches
			3.5.1 Approaches Employing the 3D Pharmacophore Concept with Molecular Docking and MD Simulations
			3.5.2 Integrated Pharmacophore and Docking-based Virtual Screening
		3.6 Summary
		References
Part B. Matrix Metalloproteinases and Their Inhibitors
	4. Collagenases and Their Inhibitors
		Contents
		Abstract
		4.1 Introduction
		4.2 Structural Overview of Collagenases
		4.3 Pathophysiology and Collagenases
		4.4 Potent MMP Inhibitors Tested Clinically
		4.5 Collagenase Inhibitors
			4.5.1 Hydroxamate-Based Inhibitors
			4.5.2 Carboxylic Acid-Based Inhibitors
			4.5.3 Thiol and Mercaptosulfide-Based Inhibitors
			4.5.4 Phosphonate-Based Inhibitors
			4.5.5 N-Hydroxyurea-Based Inhibitors
			4.5.6 Hydrazide-Based Inhibitors
			4.5.7 N-Hydroxyformamide-Based Inhibitors
			4.5.8 Squaric Acid-Based Inhibitors
			4.5.9 Pyrimidine-2,4,6-Trione-Based Inhibitors
			4.5.10 Miscellaneous Collagenase Inhibitors
		4.6 Summary
		References
	5. Gelatinases and Their Inhibitors
		Contents
		Abstract
		5.1 Introduction
		5.2 General Structure of Gelatinases
			5.2.1 Signal Peptide Domain
			5.2.2 Pro-Domain
			5.2.3 Catalytic Domain
			5.2.4 Fibronectin Domain
			5.2.5 Hemopexin Domain
		5.3 Role of Gelatinases in Different Diseases
			5.3.1 Gelatinases in Cancer
			5.3.2 Gelatinases in Neurological Disorders
			5.3.3 Gelatinases in Cardiovascular Diseases
			5.3.4 Gelatinases in Lung Diseases
			5.3.5 Gelatinases in Arthritic Diseases
			5.3.6 Gelatinases in Diabetes Mellitus
		5.4 Inhibitors of Gelatinases
			5.4.1 Hydroxamate-Based Inhibitors
			5.4.2 Non-Hydroxamate-Based Inhibitors
				5.4.2.1 Carboxylic Acid-Based Inhibitors
				5.4.2.2 Thiols and Mercaptosulfide Gelatinase Inhibitors
				5.4.2.3 Phosphonate-Based Inhibitors
				5.4.2.4 N-Hydroxyformamides-Based Inhibitors
				5.4.2.5 Pyrimidine-2,4,6-Triones-Based Inhibitors
		5.5 Summary
		References
	6. Stromelysins and Their Inhibitors
		Contents
		Abstract
		6.1 Introduction
		6.2 Pathophysiology of Stromelysins
		6.3 Hydroxamate-Based Stromelysin Inhibitors
		6.4 Carboxylic Acid-Based Stromelysin Inhibitor
		6.5 Thiol- and Mercaptosulfide-Based Stromelysin Inhibitors
		6.6 Phosphonate-Based Stromelysin Inhibitors
		6.7 N-Hydroxyurea-Based Stromelysin Inhibitors
		6.8 Hydrazide-Based Stromelysin Inhibitors
		6.9 N-Hydroxyformamide-Based Stromelysin Inhibitors
		6.10 Pyrimidine-2,4,6-Trione-Based Stromelysin Inhibitors
		6.11 Miscellaneous Stromelysin Inhibitors
		6.12 Summary
		References
	7. Matrilysin and Their Inhibitors
		Contents
		Abstract
		7.1 Introduction
		7.2 Structural Overview of Matrilysin
		7.3 Matrilysin in Different Disease Conditions
		7.4 Matrilysin Inhibitors
		7.5 Summary
		References
	8. Membrane-Type MMPs and Their Inhibitors
		Contents
		Abstract
		8.1 Introduction
		8.2 Structural Aspects of MT-MMPs
		8.3 MMP-14 Pathophysiology in Disease Conditions
			8.3.1 Cancer
			8.3.2 Cardiovascular Disease
			8.3.3 Neurodegenerative Disorders
			8.3.4 Other Diseases
		8.4 Inhibitors of MMP-14
		8.5 Summary
		References
	9. Other MMPs and Their Inhibitors
		Contents
		Abstract
		9.1 Introduction
		9.2 The Pathophysiology of Other MMPs
		9.3 Selective MMP-12 Inhibitors
		9.4 Summary
		References
Part C. Modeling of MMP Inhibitors
	10. Modeling Inhibitors of Collagenases
		Contents
		Abstract
		10.1 Introduction
		10.2 Structural Aspects of Collagenases
		10.3 X-Ray Crystal Structure and NMR Solution Structures of Collagenases
		10.4 Ligand- and Structure-Based Drug Design Strategies of Collagenase Inhibitors
			10.4.1 Ligand- and Structure-Based Drug Design Strategies of MMP-1 Inhibitors
			10.4.2 Ligand- and Structure-Based Drug Design Strategies of MMP-8 Inhibitors
			10.4.3 Ligand- and Structure-Based Drug Design Strategies of MMP-13 Inhibitors
		10.5 Summary
		References
	11. Modeling Inhibitors of Gelatinases
		Contents
		Abstract
		11.1 Introduction
		11.2 Design Strategies for Gelatinase Inhibitors
			11.2.1 Catalytic Domain Binding
				11.2.1.1 Zinc Binding
				11.2.1.2 Non-Zinc Binding
			11.2.2 Non-Catalytic Inhibitors
		11.3 QSAR Approaches in the Designing of Gelatinase (MMP-2 and MMP-9) Inhibitors
		11.4 Designing Gelatinase (MMP-2 and MMP-9) Inhibitors Using the Molecular Docking Technique
		11.5 Summary
		References
	12. Modeling Inhibitors of Stromelysins
		Contents
		Abstract
		12.1 Introduction
		12.2 Structural Aspects of Stromelysins
		12.3 X-Ray Crystal Structure and NMR Solution Structures of Stromelysins
		12.4 Ligand- and Structure-Based Drug Design Strategies on Stromelysin Inhibitors
		12.5 Summary
		References
	13. Modeling Inhibitors of Matrilysin
		Contents
		Abstract
		13.1 Introduction
		13.2 Structural Aspects of MMP-7 and MMP-26
		13.3 X-Ray Crystal Structure and NMR Solution Structures of Matrilysins
		13.4 Ligand- and Structure-Based Drug Design Strategies on Matrilysin Inhibitors
		13.5 Summary
		References
	14. Modeling Inhibitors of Membrane-Type MMPs
		Contents
		Abstract
		14.1 Introduction
		14.2 Structural Aspects of MT-MMPs
		14.3 X-Ray Crystal Structure and NMR Solution Structures of MT-MMPs
		14.4 Ligand- and Structure-based Drug Design Strategies of MT-MMP Inhibitors
		14.5 Summary
		References
	15. Modeling Inhibitors of Other MMPs
		Contents
		Abstract
		15.1 Introduction
		15.2 Structural Aspects of MMP-12
		15.3 X-Ray Crystal Structures and NMR Solution Structures of MMP-12
		15.4 Ligand- and Structure-Based Drug Design Strategies on MMP-12 Inhibitors
		15.5 Summary
		References
Part D. Conclusion and Future Perspective
	16. Conclusion and Future Perspectives
		References
Index