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)

The capacity of inflammatory cell-derived matrix metalloproteinases (MMPs) to cleave tissue factor pathway inhibitor (TFPI) and alter its activity was investigated. MMP-7 (matrilysin) rapidly cleaved TFPI to a major 35-kDa product. In contrast, MMP-1 (collagenase-1), MMP-9 (gelatinase B), and MMP-12 (macrophage elastase) cleaved TFPI into several fragments including the 35-kDa band. However, rates of cleavage were most rapid for MMP-7 and MMP-9. NH(2)-terminal amino acid sequencing revealed that MMP-12 cleaved TFPI at Lys(20)-Leu(21)(close to Kunitz I domain and producing a 35-kDa band), Arg(83)-Ile(84) (between Kunitz I and II domains), and Ser(174)-Thr(175) (between Kunitz II and III domains). MMP-7 and MMP-9 cleaved TFPI at Lys(20)-Leu(21) with additional COOH-terminal processing. These MMPs did not cleave tissue factor (TF), factor VII, and factor Xa. Proteolytic cleavage by MMP-1, MMP-7, MMP-9, and MMP-12 resulted in considerable loss of TFPI activity. These observations indicate specific cleavage of TFPI by MMPs, which broadens their substrate profile. Co-localization of MMPs, TF, and TFPI in atherosclerotic tissues suggests that release of MMPs from inflammatory cell leukocytes may effect TF-mediated coagulation.
 ...
PMID:Matrix metalloproteinases cleave tissue factor pathway inhibitor. Effects on coagulation. 1085 19

We report the development and validation of a novel suite of programs, FITTED 1.0, for the docking of flexible ligands into flexible proteins. This docking tool is unique in that it can deal with both the flexibility of macromolecules (side chains and main chains) and the presence of bridging water molecules while treating protein/ligand complexes as realistically dynamic systems. This software relies on a genetic algorithm to account for the flexibility of the two molecules as well as the location of bridging water molecules. In addition, FITTED 1.0 features a novel application of a switching function to retain or displace key water molecules from the protein-ligand complexes. Two independent modules, ProCESS and SMART, were developed to set up the proteins and the ligands prior to the docking stage. Validation of the accuracy of the software was achieved via the application of FITTED 1.0 to the docking of inhibitors of HIV-1 protease, thymidine kinase, trypsin, factor Xa, and MMP to their respective proteins.
 ...
PMID:Docking ligands into flexible and solvated macromolecules. 1. Development and validation of FITTED 1.0. 1730 29

In the last 20 years the advent of new technologies, such as high-throughput screening (HTS) and combinatorial chemistry, has produced new tools for the discovery of biologically active molecules. In the past decade, fragment-based drug discovery has emerged as a more rational and focused approach that concentrates on the quality, rather than the quantity, of hits and leads. The principles behind this strategy are different from those that represented the basis of conventional HTS. The starting point of this approach is always a small chemical entity (typically MW 150-200), a fragment, with low affinity for the selected target. Fragments should satisfy key features such as diversity, reduced structural complexity, aqueous solubility and availability. Because of their small size, they occupy a smaller region of chemical space if compared with classical HTS compounds; hence, fragment libraries provide a good diversity with a relatively low number of compounds. Classical biochemical assays are often not suitable to detect the low binding affinities involved, so some well known biophysical techniques, such as nuclear magnetic resonance and x-ray, have been opportunely modified in order to render them able to perform the task. When selecting fragments suitable for subsequent optimization, a useful parameter has been introduced, the ligand efficiency, which is defined as the free energy of binding divided by the non-hydrogen atom count. Once selected, a fragment must undergo a heavy elaboration to improve binding affinity, at the same time acquiring drug-like properties. There are two main ways to go on at this point. The most common one is the so-called 'fragment evolution', consisting of a stepwise and systematic addition of chemical functionalities to the starting fragment core, together with a continuous feedback for pharmacological and physicochemical properties. The second one, less common but with great potential, is 'fragment linking': when two or more fragment hits are found to bind in adjacent regions of the target protein, they can be linked through appropriate spacers to rapidly produce a single molecule with much higher binding affinity. Two representative case histories are described: Abbott's ABT 518, an MMP (matrix metalloproteinase) inhibitor, and Eli-Lilly's LY-517717, an inhibitor of factor Xa serine protease. In addition, a list of molecules claimed to be derived from fragment approach and currently undergoing clinical trials is presented.
 ...
PMID:Fragment-based approach to drug lead discovery: overview and advances in various techniques. 1858 53