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The Gelatinases and Their Inhibitors: The Structure–Activity Relationships

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Matrix Metalloproteinase Inhibitors

Part of the book series: Experientia Supplementum ((EXS,volume 103))

Abstract

The interest in gelatinases is increased because of their association in diverse human diseases, though the relationship between MMP expression and disease progression is very complex and varies in cell to cell. Targeting gelatinases in disease treatment is complicated by the fact that gelatinases are indispensable for normal development and physiology due to their multifunctionality, possible functional redundancy, context-dependent expression, and activity. They are secreted as inactive zymogens which are processed to become active by removal of N-terminal propeptide. The folded conformation of zymogen is required to keep the gelatinases in its latency. Acting on a broad spectrum of extracellular substrates, the gelatinases (both MMP-2 and MMP-9) are critical to the biological processes. Three-dimensional structures of gelatinase–inhibitor complexes and inhibition profiles of compounds screened on them provide an invaluable source to gain insight into the structural determinants as well as functional selectivity. The quest for selective MMP inhibitors (MMPIs) still remains a challenge in search of successful clinical candidates. An increased understanding of the structure, regulation, and function of the individual MMPs will likely lead to more effective strategies in the development of highly selective inhibitors for any given MMP that can then be exploited to achieve the desired drugs.

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Abbreviations

APMA:

4-Aminophenylmercuric acetate

GAG:

Glycosaminoglycan

GA:

Genetic algorithm

LRP:

Low-density lipoprotein receptor-related protein

NGAIL:

Neutrophil gelatinase-associated lipocalin

MLR:

Multiple linear regression

MMPs:

Matrix metalloproteinases

ROS:

Reactive oxygen species

TGFβ:

Transforming growth factor β

TIMPs:

Tissue inhibitors of metalloproteinases

VEGF:

Vascular endothelial growth factor

VCAM:

Vascular cell adhesion molecule

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Acknowledgment

Work is supported by grants NBA2007 of DBT and CLP261 of NTRF, India.

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  1. Drug Development Diagnostics and Biotechnology Division, Department of Physiology, CSIR-Indian Institute of Chemical Biology, 4, Raja S.C.Mullick Road, Jadavpur, Kolkata, 700032, India

    Snehasikta Swarnakar, Amartya Mishra & Susri Ray Chaudhuri (Guha)

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Correspondence to Snehasikta Swarnakar .

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    Satya Prakash Gupta

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Swarnakar, S., Mishra, A., Chaudhuri (Guha), S.R. (2012). The Gelatinases and Their Inhibitors: The Structure–Activity Relationships. In: Gupta, S. (eds) Matrix Metalloproteinase Inhibitors. Experientia Supplementum, vol 103. Springer, Basel. https://doi.org/10.1007/978-3-0348-0364-9_3

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