Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A novel strategy to understand affinity and selectivity for enzyme inhibitors using information from ligands and target protein 3D structures is described. It was applied to 2-arylsulfonyl-1,2,3, 4-tetrahydro-isoquinoline-3-carboxylates and -hydroxamates as inhibitors of the matrix metalloproteinases MMP-3 (stromelysin-1) and MMP-8 (human neutrophil collagenase). As the first step, consistent and predictive 3D-QSAR models were derived using CoMFA, CoMSIA, and GRID/Golpe approaches, leading to the identification of binding regions where steric, electronic, or hydrophobic effects are important for affinity. These models were validated using multiple analyses using two or five randomly chosen cross-validation groups and randomizations of biological activities. Second, 3D-QSAR models were derived based on the affinity ratio IC(50)(MMP-8)/IC(50)(MMP-3), allowing the identification of key ligand determinants for selectivity toward one of both enzymes. In addition to this ligands' view, the third step encompasses a chemometrical approach based on principal component analysis (PCA) of multivariate GRID descriptors to uncover the major differences between both protein binding sites with respect to their GRID probe interaction pattern. The resulting information, based on the accurate knowledge of the target protein 3D structures, led to a consistent picture in good agreement with experimentally observed differences in selectivity toward MMP-8 or MMP-3. The interpretation of all three classes of statistical models leads to detailed SAR information for MMP inhibitors, which is in agreement with available data for binding site topologies, ligand affinities, and selectivities. Thus the combined chemical analyses provide guidelines and accurate activity predictions for designing novel, selective MMP inhibitors.
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PMID:Affinity and selectivity of matrix metalloproteinase inhibitors: a chemometrical study from the perspective of ligands and proteins. 1057 15

EAU is characterized by breakdown of the blood-retinal barrier and extravasation of leucocytes into retinal tissue leading to destruction of photoreceptor cells. Matrix metalloproteinases (MMP) have been implicated in trafficking of cells into tissues, but their role in inflammatory eye disease is unclear. A synthetic MMP inhibitor, BB-1101, was administered subcutaneously, from either day 0 or day 7, to Lewis rats challenged with bovine S-antigen to induce EAU. When given up to day 14, BB-1101 reduced the incidence of disease and delayed the day of onset of clinical disease. When administered from day 7 until day 21, EAU was completely abrogated. A quantitative polymerase chain reaction (PCR) assay showed an increase of both matrilysin (MMP-7), neutrophil collagenase (MMP-8) and macrophage metalloproteinase (MMP-12) in retinas from EAU animals compared with naive controls. These enzymes are produced by activated leucocytes and act on components of the basement membrane. These results therefore implicate these MMP as integral to the development of pathology in EAU.
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PMID:The matrix metalloproteinase inhibitor BB-1101 prevents experimental autoimmune uveoretinitis (EAU). 1059 53

Matrix metalloproteinases (MMPs, matrixins) are a family of homologous zinc endopeptidases that may play a very important role in many physiological and pathological processes, e.g., the initiation of angiogenesis. Two new matrixin inhibitors were synthesized and characterized. A thiol inhibitor MAG-283 had IC(50) values of 480, 3, 280, 14, 1.1, and 2.3 nM against human interstitial collagenase (MMP-1), gelatinase A (MMP-2), stromelysin (MMP-3), matrilysin (MMP-7), neutrophil collagenase (MMP-8), and gelatinase B (MMP-9), respectively. A sulfodiimine inhibitor YLL-224 had IC(50) values of 180, 63, 4500, 210, 5.9, and 44 nM against MMP-1, -2, -3, -7, -8, and -9, respectively. Human skin microvascular endothelial cells were treated with these two compounds in culture. These inhibitors at very low micromolar concentrations suppressed proliferation of the endothelial cells stimulated by acidic fibroblast growth factor and vascular endothelial growth factor. They also partially blocked cell invasion through type IV collagen. These results suggested a correlation between the anti-metalloenzyme activity and the effects of these inhibitors on the growth and invasion of endothelial cells.
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PMID:New thiol and sulfodiimine metalloproteinase inhibitors and their effect on human microvascular endothelial cell growth. 1092 54

The effects of plasma proteins on controlling the activity of matrix metalloproteinases (MMPs, matrixins) have been the focus of numerous studies, although only a few have examined the influence of matrixins on plasma proteins. Recently, it has been shown that MMPs may play a role in the degradation of fibrin. We have now investigated the role of collagenase-2 (MMP-8), macrophage elastase (MMP-12), collagenase-3 (MMP-13), and membrane type 1-matrix metalloproteinase (MT1-MMP, MMP-14) in the degradation of fibrinogen and Factor XII of the plasma clotting system. Our data demonstrate that the catalytic domains of MMP-8, MMP-12, MMP-13, and MMP-14 can proteolytically process fibrinogen and, with the exception of MMP-8, also inactivate Factor XII (Hageman factor). We have identified the amino termini of the major protein fragments. Cleavage of fibrinogen occurred in all chains and resulted in significantly impaired clotting. Moreover, rapid proteolytic inactivation of Factor XII (Hageman factor) by MMP-12, MMP-13, and MMP-14 was noted. These results support the hypothesis of an impaired thrombolytic potential of MMP-degraded Factor XII in vivo. MMP-induced degradation of fibrinogen supports a plasmin-independent fibrinolysis mechanism. Consequently, degradation of these proteins may be important in inflammation, atherosclerosis, and angiogenesis, all of which are known to be influenced by MMP activity.
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PMID:Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII. 1093 Mar 99

Periodontal inflammation is characterized by irreversible degradation of periodontal ligament collagen fibers leading to loss of tooth attachment. Cultured gingival keratinocytes and fibroblasts express, in vitro, various matrix metalloproteinases (MMPs) which can degrade fibrillar collagens. We hypothesized that several MMPs are also synthesized in vivo by sulcular epithelium, and analyzed the collagenolytic MMPs (MMP-2, -8, -13, and -14) and matrilysin (MMP-7) in gingival tissue specimens and gingival crevicular fluid from adult and localized juvenile periodontitis patients by in situ hybridization, immunohistochemistry, and Western immunoblotting. MMP-2, -7, -8, and -13 were expressed in gingival sulcular epithelium. MMP-7 and -13 were also located in fibroblasts and macrophages, and MMP-8 in neutrophils. MMP-8- and -13-positive cells/mm2 were higher in periodontitis gingiva when compared with healthy control tissue (p < 0.01). In periodontal diseases, gingival sulcular epithelium expresses several, rather than a single, collagenolytic MMPs, and this proteolytic cascade is evidently responsible for the tissue destruction characteristic of adult and juvenile periodontitis.
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PMID:The in vivo expression of the collagenolytic matrix metalloproteinases (MMP-2, -8, -13, and -14) and matrilysin (MMP-7) in adult and localized juvenile periodontitis. 1120 Oct 47

The 5,5-disubstitutedpyrimidine-2,4,6-triones represent a new class of MMP inhibitors showing selectivity for the gelatinases A and B, collagenase-3, and human neutrophil collagenase. The SAR presented here is in good agreement with an X-ray structure of compound 5 bound to the catalytic domain of stromelysin-1. While of the barbiturate structural class, compound 5 did not show any toxic or sedative effects.
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PMID:Novel 5,5-disubstitutedpyrimidine-2,4,6-triones as selective MMP inhibitors. 1132 2

The aim of the study is to evaluate MMP-1, MMP-8 and MMP-9 serum levels in patients with adrenal tumors prior to and after surgery. Metalloproteinase-1 (MMP-1), MMP-8 and MMP-9 serum levels were evaluated in 43 patients operated on at our clinic between 1997-1999. Forty-one (95.3%) patients underwent adrenalectomy. Two (4.7%) patients were disqualified from surgery due to infiltration of adjacent tissues. MMP-1, MMP-8 and MMP-9 serum levels were determined at the admission and in case of surgery again one month after the operation. ELISA assay (K&D) was applied. Tumor type was determined on the basis of clinical, hormonal and histopathological examination. The correlation between MMP levels and tumor sizes was also evaluated. Patients were divided into 6 groups. Group I included 11 patients with adrenocortical carcinoma (4 with Cushing's syndrome and 7 with incidentalomas); group II--6 patients with benign hormonally active adrenocortical adenoma (4 with Cushing's syndrome and 2 with Conn's syndrome); group III--patients with benign, hormonally inactive adenocortical adenoma; group IV--6 patients with benign, hormonally active phaeochromocytoma; group V--4 patients with hormonally inactive phaeochromocytoma; group VI--5 patients with hormonally inactive adrenal tumors of extraglandular origin (2 myolipomas, 2 fibrolipomas, 1 hammartoma). The control group comprised 10 healthy individuals. Increased MMP-8 and MMP-9 levels were noted in patients with benign and malignant adrenal tumors. No increase of MMP levels was found in patients with tumors of extraglandular origin. The increased MMP-8 and MMP-9 levels occurred most frequently in patients with adrenocortical and hormonally active adrenomedullar cancer, and most rarely in patients with hormonally active adrenocortical tumors. MMP-8 and MMP-9 serum levels did not significantly differ between patients with adrenocortical incidentaloma cancers and in patients with benign incidentalomas. MMP-8 and MMP-9 levels were not increased in patients with inoperable adrenocortical cancers. Serum MMP-1 levels were not increased in patients with benign and malignant adrenal tumors. After surgery, MMP-8 and MMP-9 levels decreased significantly in patients with adrenocortical cancers, whereas the decrease of these MMPs in patients with benign tumors, although noticeable, was not statistically significant. MMP-8 and MMP-9 levels decreased significantly in all patients with increased preoperative levels, although they remained higher than the maximum normal values only in few patients (in 7 and 2 patients, respectively). No correlation between the levels of evaluated MMPs and tumor sizes were found.
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PMID:Evaluation of MMP-1, MMP-8, MMP-9 serum levels in patients with adrenal tumors prior to and after surgery. 1147 91

MMP-2 is a member of the matrix metalloproteinase family that has been implicated in tumor cell metastasis and angiogenesis. Here, we describe the solution structure of a catalytic domain of MMP-2 complexed with a hydroxamic acid inhibitor (SC-74020), determined by three-dimensional heteronuclear NMR spectroscopy. The catalytic domain, designated MMP-2C, has a short peptide linker replacing the internal fibronectin-domain insertion and is enzymatically active. Distance geometry-simulated annealing calculations yielded 14 converged structures with atomic root-mean-square deviations (r.m.s.d.) of 1.02 and 1.62 A from the mean coordinate positions for the backbone and for all heavy atoms, respectively, when 11 residues at the N-terminus are excluded. The structure has the same global fold as observed for other MMP catalytic domains and is similar to previously solved crystal structures of MMP-2. Differences observed between the solution and the crystal structures, near the bottom of the S1' specificity loop, appear to be induced by the large inhibitor present in the solution structure. The MMP-2C solution structure is compared with MMP-8 crystal structure bound to the same inhibitor to highlight the differences especially in the S1' specificity loop. The finding provides a structural explanation for the selectivity between MMP-2 and MMP-8 that is achieved by large inhibitors.
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PMID:Solution structure and backbone dynamics of the catalytic domain of matrix metalloproteinase-2 complexed with a hydroxamic acid inhibitor. 1214 39

Monocyte chemoattractant protein (MCP)-3 is inactivated upon cleavage by the matrix metalloproteinase (MMP) gelatinase A (MMP-2). We investigated the susceptibility to proteolytic processing of the 4 human MCPs by 8 recombinant MMPs to determine whether MCP-3 is an isolated example or represents a general susceptibility of chemokines to proteolytic inactivation by these important inflammatory proteases. In addition to MMP-2, MCP-3 is efficiently cleaved by membrane type 1 (MT1)-MMP, the cellular activator of MMP-2, and by collagenase-1 and collagenase-3 (MMP-1, MMP-13) and stromelysin-1 (MMP-3). Specificity was shown by absence of cleavage by matrilysin (MMP-7) and the leukocytic MMPs neutrophil collagenase (MMP-8) and gelatinase B (MMP-9). The closely related chemokines MCP-1, MCP-2, and MCP-4 were not cleaved by MMP-2 or MT1-MMP, but were cleaved by MMP-1 and MMP-3 with varying efficiency. MCPs were typically cleaved between residues 4 and 5, but MCP-4 was further processed at Val7-Pro8. Synthetic MCP analogs corresponding to the MMP-cleaved forms bound CC chemokine receptor (CCR)-2 and CCR-3, but lacked chemoattractant activity in pre-B cells transfected with CCR-2 and CCR-3 or in THP-1 monocytic cells, a transformed leukemic cell line. Moreover, the truncated products of MCP-2 and MCP-4, like MCP-3, were potent antagonists of their cognate CC chemokine receptors in transwell cell migration assays in vitro. When they were injected 24 hours after the initiation of carrageenan-induced inflammation in rat paws, their in vivo antagonist activities were revealed by a greater than 66% reduction in inflammatory edema progression after 12 hours. We propose that MMPs have an important role in modulating inflammatory and immune responses by processing chemokines in wound healing and in disease.
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PMID:Matrix metalloproteinase processing of monocyte chemoattractant proteins generates CC chemokine receptor antagonists with anti-inflammatory properties in vivo. 1214 83

UV irradiation leads to distinct changes in skin connective tissue by degradation of collagen, for example. Many of these alterations in the extracellular matrix are mediated by MMPs (matrix metalloproteinases) with reduced content of their antagonist TIMPs (tissue inhibitors of metalloproteinases). Potential candidates to reduce MMP activity in the skin after solar stimulation were examined. The influence of vitamin C, vitamin E and the flavonoids AGR (alpha-glucosylrutin) and 8-prenylnaringenine on the MMP and TIMP expression was investigated. Human dermal fibroblasts were incubated with these additives and irradiated with UVA [10 J cm(-2)]. The gene expression of MMP-1 (collagenase-1) and TIMP-1, the protein expression of MMP-1, MMP-2 (gelatinase-A), TIMP-1 and TIMP-2 as well as the enzyme activity of MMP-1 and MMP-2 were examined. AGR and vitamins C and E were shown to reduce MMP expression and activity, whereas 8-prenylnaringenine appeared to be responsible for the opposite effect. None of the substances considerably influenced the TIMP levels. AGR represented the most effective additive in reducing the collagenase protein expression to 60% and may be useful to level out the MMP activity in the skin after sun exposure. Furthermore, no protein expression of MMP-8, MMP-9, MMP-12 and MMP-13 could be detected.
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PMID:Influence of flavonoids and vitamins on the MMP- and TIMP-expression of human dermal fibroblasts after UVA irradiation. 1265 86


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