Poster Presenter

Identification of Specific Inhibitor Ligands for MMP-13 Hemopexin Domain: Possible Role as Anti-Arthritic Agents
Roopa Kothapalli, Asif M Khan, Yap Seng Chong, Loganath Annamalai
Singapore


MMP-13 (collagenase 3) is a zinc-dependent protease which catalyses the cleavage of type II collagen, the main structural component of articular cartilage. It is not found in normal adult tissues but is expressed by chondrocytes and synovial cells in the joints and articular cartilage of patients with rheumatoid arthritis (RA) and osteoarthritis (OA). This property along with studies of OA in genetically modified mice renders MMP-13 as the direct cause of irreversible cartilage damage in arthritic conditions. Moreover it was observed that the 4 functional domains present in the enzyme cleave the peptide bond at 775-776 in all three strands of the mature triple helical collagen molecules. Although the catalytic domains can hydrolyze the non-collagenous proteins and synthetic substrates only, the hemopexin domain appears to be specific in cleaving the triple helical collagen molecules. Since early studies demonstrate that broad-spectrum MMP inhibitors to the catalytic domain have dose limiting toxicity in the form of musculoskeletal syndrome (MSS), we have in this study designed four potential small molecule inhibitors to the hemopexin domain of MMP-13. Based on the cheminformatics approach we have been able to design 4 drug-like molecules which may have the propensity to inhibit the collagenase 3 activity. These novel molecules which were identified through structure-based drug design include 1 N-benzyl-N-methyl-6-morpholi nopyridine-3-sulfonamide,7-((6,7-dimethoxyquinazolin-4-ylamino)methyl)benzo[d][1,3]dioxole-4-sulfonic acid, 2-(hydroxyamino)-2-oxoethyl 2-((2-chlorophenoxy)methyl)-5-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate,2-hydroxy-4,6-dioxo-1,4,5,6-tetrahydropyrimidin-5-yl 2-((2-chlorophenoxy)methyl)-5-methyl-6-oxo-1,6-dihydropyrimidine-4-carboxylate. It is envisaged that these four novel molecules could be evaluated as anti-arthritic agents which could ameliorate these inflammatory conditions.