Review
Matrix metalloproteinases (MMPs): Chemical–biological functions and (Q)SARs

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Abstract

Matrix metalloproteinases (MMPs) are a large family of calcium-dependent zinc-containing endopeptidases, which are responsible for the tissue remodeling and degradation of the extracellular matrix (ECM), including collagens, elastins, gelatin, matrix glycoproteins, and proteoglycan. They are regulated by hormones, growth factors, and cytokines, and are involved in ovarian functions. MMPs are excreted by a variety of connective tissue and pro-inflammatory cells including fibroblasts, osteoblasts, endothelial cells, macrophages, neutrophils, and lymphocytes. These enzymes are expressed as zymogens, which are subsequently processed by other proteolytic enzymes (such as serine proteases, furin, plasmin, and others) to generate the active forms. Matrix metalloproteinases are considered as promising targets for the treatment of cancer due to their strong involvement in malignant pathologies. Clinical/preclinical studies on MMP inhibition in tumor models brought positive results raising the idea that the development of strategies to inhibit MMPs may be proved to be a powerful tool to fight against cancer. However, the presence of an inherent flexibility in the MMP active-site limits dramatically the accurate modeling of MMP–inhibitor complexes. The interest in the application of quantitative structure–activity relationships (QSARs) has steadily increased in recent decades and we hope it may be useful in elucidating the mechanisms of chemical–biological interactions for this enzyme. In the present review, an attempt has been made to explore the in-depth knowledge from the classification of this enzyme to the clinical trials of their inhibitors. A total number of 92 QSAR models (44 published and 48 new formulated QSAR models) have also been presented to understand the chemical–biological interactions. QSAR results on the inhibition of various compound series against MMP-1, -2, -3, -7, -8, -9, -12, -13, and -14 reveal a number of interesting points. The most important of these are hydrophobicity and molar refractivity, which are the most important determinants of the activity.

Graphical abstract

The review highlights from the classification of this enzyme to the clinical trials of their inhibitors. A total number of 92 QSAR models (44 published and 48 new QSAR models) have also been presented. Contributions of different descriptors in the derivation of 48 new QSAR models for MMP-1–14 are shown in the figure.

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Introduction

Matrix metalloproteinases (MMPs) are a large family of calcium-dependent zinc-containing endopeptidases, which are responsible for the tissue remodeling and degradation of the extracellular matrix (ECM), including collagens, elastins, gelatin, matrix glycoproteins, and proteoglycan. MMPs are usually minimally expressed in normal physiological conditions and thus homeostasis is maintained. However, MMPs are regulated by hormones, growth factors, and cytokines, and are involved in ovarian functions. Endogenous MMP inhibitors (MMPIs) and tissue inhibitors of MMPs (TIMPs) strictly control these enzymes. Over-expression of MMPs results in an imbalance between the activity of MMPs and TIMPs that can lead to a variety of pathological disorders.1, 2, 3, 4, 5 A list of physiological and pathological processes for which MMPs have been implicated is shown in Table 1.5, 6 The earliest descriptions of MMPs were in 1949 as depolymerizing enzymes which, it was proposed, could facilitate tumor growth by making connective tissue stroma, including that of small blood vessels, more fluid. About after 13 years, the first vertebrate MMP, collagenase, was isolated and characterized as the enzyme responsible for the resorption by tadpole tail. During the next 20 years, several mammalian enzymes were partially purified, but it was not until 1985 that the field really developed when structural homologies became apparent, allowing many new members to be identified through the techniques of molecular biology.7 In a recent work, it was concluded that smoking alters the levels of matrix metalloproteinases in skin tissue, serum, and saliva, which may affect the turnover of extracellular matrix (ECM) of skin.8

Matrix metalloproteinases are excreted by a variety of connective tissue and pro-inflammatory cells including fibroblasts, osteoblasts, endothelial cells, macrophages, neutrophils, and lymphocytes. These enzymes are expressed as zymogens, which are subsequently processed by other proteolytic enzymes (such as serine proteases, furin, plasmin, and others) to generate the active forms. Under normal physiological conditions, the proteolytic activity of the MMPs is controlled at any of the following three known stages: activation of the zymogens, transcription, and inhibition of the active forms by various tissue inhibitors of MMPs (TIMPs). In pathological conditions this equilibrium is shifted toward increased MMP activity leading to tissue degradation.9, 10

MMPs have now been considered as a promising target for cancer therapy and a large number of synthetic and natural MMP inhibitors (MMPIs) have been identified as cytostatic and anti-angiogenic agents, and have begun to undergo clinical trials in view of their specific implication in malignant tissues. Although preclinical studies were compelling to encourage several clinical trials, the past years have seen a consistent number of disappointing results and/or limited success. The critical examination of previous results has prompted serious re-evaluation of MMP-inhibition strategies focusing the attention of future research on the identification of specific MMP targets in tumors at different stages of tumor progression, both in order to improve efficacy and to reduce the side-effect profile.11, 12

A search from SciFinder Scholar (2006 Edition) of the Chemical Abstract reveals that there are over 26,400 publications (journal articles, patents, and abstracts) on MMPs made during the years of 1987 and 2006 (from January 1987 to July 2006), which includes about 550 publications on MMPs-(Q)SAR [(quantitative) structure–activity relationships]. A histogram of publications on MMPs and MMPs-(Q)SAR during the years of 1987 and 2006 reflects fluctuation of interest and research intensity (Fig. 1).

Section snippets

Classification

To date at least 26 human MMPs are known (see Table 2). On the basis of their specificity, these MMPs are classified into collagenases, gelatinases, stromelysins, and matrilysins. Another subclass of MMPs is represented by the membrane-type MMPs (MT-MMPs) that additionally contain a transmembrane and intracellular domain, a membrane linker domain, or are membrane associated.7, 13, 14 A histogram for the publication of 26 MMPs during 1987–2005 is shown in Figure 2.

Structural studies

Most of the matrix metalloproteinases consist of four distinct domains, which are N-terminal pro-domain, catalytic domain, hinge region, and C-terminal hemopexin-like domain. This may be responsible for the macromolecular substrate recognition as well as for interaction with TIMPs. The membrane-type MMPs (MT-MMPs) contain an additional transmembrane domain that anchors them in the cell surface.15 The advent of high-resolution X-ray and NMR structures has provided new paradigms for the design of

Reaction mechanism

The reaction mechanism for the proteolysis by MMPs has been delineated on the basis of structural information28, 29 and shown in Figure 3.29 It is proposed that the scissile amide carbonyl coordinates to the active-site zinc(II) ion. This carbonyl is attacked by a water molecule, which is both hydrogen bonded to a conserved glutamic acid (Glu-198 in MMP-8) and coordinated to the zinc(II) ion. The water molecule donates a proton to the Glu residue that transfers it to the nitrogen of the

Active site

The active site consists of two distinct regions: a groove in the protein surface centered on the catalytic zinc ion and an S1′ specificity site that varies considerably among members of the family. Bound inhibitors adopt extended conformations within the groove, make several β-structure-like hydrogen bonds with the enzyme, and provide the fourth ligand for the catalytic zinc ion. The S1′ subset apparently plays a significant role in determining the substrate specificity in the active enzymes.

Substrate selectivity

It has been established that the various MMPs exhibit different selectivities for the various matrix proteins. Thus, it is of interest in understanding such substrate selectivity to identify optimized peptide substrates for assay development as well as to design the selective MMP inhibitors. Some studies have been performed to determine the sequence of the cleavage site in protein substrates for individual enzymes.32, 33, 34 In the majority of cases, the variation of substitution provides a

MMPs and apoptosis

Apoptosis, also known as programmed cell death (PCD), is an extremely well-ordered process by which unwanted, defective, or damaged cells are rapidly and selectively eliminated from the body. MMPs play an intriguing role in PCD, showing both apoptotic and anti-apoptotic action (Table 4).40 MMPs affect cell survival and proliferation both positively and negatively by regulating ‘survival signals’ generated by specific adhesive events; these particular effects of MMPs may reflect the differences

MMP inhibitors

The development of synthetic inhibitors of MMPs has relied on the peptide sequence, recognized by the targeted protease, to which have been grafted different chemical functionalities able to interact potently with the zinc ion of the active site.20 The requirements for a molecule to be an effective inhibitor of the MMP class of enzymes are: (i) a functional group [e.g., hydroxamate (CONH–O), carboxylate (COO), thiolate (S), phosphinyl (PO2-), etc.] capable of chelating the active-site

Hydroxamates

Most of the MMP inhibitors developed by pharmaceutical companies belong to the hydroxamate category. This choice was actually based on the early studies, which suggest that the extremely potent inhibitors of MMPs can be obtained by grafting a hydroxamate moiety to a suitable peptide sequence.20 A SAR study for a series of hydroxamic acids (MMP inhibitors) with a quaternary-hydroxyl group at P1 suggested the following10:

  • (a)

    Stereochemical orientation at P1 is crucial for the activity. For example,

Quantitative structure–activity relationships (QSARs)

Quantitative structure–activity relationships (QSARs) are one of the well-developed areas in computational chemistry. In the past 44 years, the use of QSAR, since the advent of this methodology,78 has become increasingly helpful in understanding many aspects of chemical–biological interactions in drug and pesticide research, as well as in the areas of toxicology.79 This method is useful in elucidating the mechanisms of chemical–biological interaction in various biomolecules, particularly

MMP inhibitors in clinical trials

A number of MMP inhibitors are in various stages of clinical development especially for the treatment of cancer and arthritis, and listed in Table 46.

Conclusion

Matrix metalloproteinases are considered as promising targets for the treatment of cancer due to their strong involvement in malignant pathologies. Clinical/preclinical studies on MMP inhibition in tumor models brought positive results raising the idea that the development of strategies to inhibit MMPs may be proved to be a powerful tool to fight against cancer. Despite the known 3D structure of several catalytic domains of MMPs, the development of highly specific synthetic active-site-directed

Rajeshwar P. Verma was born in 1966 in Barh (India). He received his M.Sc. (1988) and Ph.D. (1992) degrees in chemistry from Magadh University, Bodh-Gaya. He spent a year at the same university as a postdoctoral fellow with Professor K. S. Sinha. He joined Roorkee University (now IIT Roorkee) as a research associate and worked with Professor S.M. Sondhi (1993–1997). He also worked as a Lecturer of Chemistry at Gurukula Kangri University, Hardwar (1994–1995). He won a Research Associateship

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    Rajeshwar P. Verma was born in 1966 in Barh (India). He received his M.Sc. (1988) and Ph.D. (1992) degrees in chemistry from Magadh University, Bodh-Gaya. He spent a year at the same university as a postdoctoral fellow with Professor K. S. Sinha. He joined Roorkee University (now IIT Roorkee) as a research associate and worked with Professor S.M. Sondhi (1993–1997). He also worked as a Lecturer of Chemistry at Gurukula Kangri University, Hardwar (1994–1995). He won a Research Associateship Award in December 1994 from the Council of Scientific and Industrial Research, New Delhi (India). In 1997, he moved to Pomona College to join the renowned QSAR research group of Professor Corwin Hansch and Cynthia Selassie, working as a postdoctoral research associate. Dr. Verma’s research interests include the following: isolation, characterization, and synthesis of natural products derived from medicinal plants; chemistry of isothiocyanates; synthesis of biologically important heterocycles and phenolic compounds; quantitative structure–activity relationships (QSAR) and computer-assisted drug design.

    Corwin Hansch received his undergraduate education at the University of Illinois and his Ph.D. degree in organic chemistry from New York University in 1944. After working with the Du Pont Co., first on the Manhattan Project and then in Wilmington, DE, he joined the Pomona College faculty in 1946. He has remained at Pomona except for two sabbaticals: one at the Federal Institute of Technology in Zurich, Switzerland, with Professor Prelog and the other at the University of Munich with Professor Huisgen. The Pomona group published the first paper on the QSAR approach relating chemical structure with biological activity in 1962. Since then, QSAR has received widespread attention. He is an honorary fellow of the Royal Society of Chemistry and recently received the ACS Award for Computers in Chemical and Pharmaceutical Research for 1999.

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