Matrix Metalloproteinase Focused Library

Matrix metalloproteinases (MMPs) are a large family of zinc-dependent endoproteinases. They are found in all kingdoms of life and belong to the metzincin superfamily of metalloproteinases characterized by the presence of a catalytic zinc atom in their active center. At least 25 different vertebrate MMPs have been identified, 24 of which are present in humans: collagenases (MMP type - 1, 8, 13), gelatinases (MMP 2, 9), MT-MMPs (MMP 14, 15, 16, 17, 24, 25), stromelysins (MMP 3, 10, 11), matrilysin (MMP 7, 26) and other types 12, 19-21, 23A / B, 27, 28 [1-2].

MMPs have long been used as promising targets for treatment of various pathologies, including cancer (tumor angiogenesis and metastases), osteoarthritis (OA), inflammation, periodontitis, vascular disease, remodeling after myocardial infarction, neurodegenerative diseases and neuropsychiatric disorders [2-3]. Development of MMP inhibitors usually proceeded along the path of inhibition of the active site of Zn2+, but was often misinterpreted due to the lack of specificity and subsequent side effects [3].

Taking this into account, Life Chemicals has designed its Screening Library of potential matrix metalloproteinase inhibitors based on rigid selection by structural and physicochemical parameters.

Initially, about 30,000 reference compounds with known MMPs blocking activity were obtained from the CHEMBL database. The compounds have been filtered to leave only those possessing moderate and high activity against MMPs that narrowed down a set to 7,085 compounds. At the next step, a similarity search of the reference set has been performed against the Life Chemicals HTS Compound Collection, employing 2D molecular fingerprints and two similarity metrics (Tanimoto > 0.75). Afterwards, the Lipinski’s Rule of Five filters were applied to leave only drug-like compounds. In addition, PAINS compounds, as well as those with "bad" and reactive groups, have been discarded.

The Matrix Metalloproteinase Focused Library contains over 2,000 screening compounds with predicted activity against the following targets:

  • 1,2-dihydroxy-3-keto-5- methylthiopentene dioxygenase

  • 72 kDa type IV collagenase

  • ADAMTS5

  • Collagenase

  • Collagenase 3

  • Matrix metalloproteinase 1

  • Matrix metalloproteinase 2

  • Matrix metalloproteinase 3

  • Matrix metalloproteinase 9

  • Matrix metalloproteinase 11

  • Matrix metalloproteinase 12

  • Matrix metalloproteinase 13

  • Matrix metalloproteinase 14

  • Matrix metalloproteinase 15

 

Figure 1. Example of representative molecules from the Matrix Metalloproteinase Focused Library selected on the base of the reference compound set.

 

References:

  1. Fanjul-Fernández M, Folgueras AR, Cabrera S, López-Otín C. Matrix metalloproteinases: evolution, gene regulation and functional analysis in mouse models // Biochim Biophys Acta. 2010 Jan;1803(1):3-19.

  2. Rydlova M1, Holubec L Jr, Ludvikova M Jr, Kalfert D, Franekova J, Povysil C, Ludvikova M. Biological activity and clinical implications of the matrix metalloproteinases // Anticancer Res. 2008 Mar-Apr;28(2B):1389-97.

  3. Fields GB. New strategies for targeting matrix metalloproteinases // Matrix Biol. 2015 May- Jul;44-46:239-46.

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