MOLECULAR DYNAMICS SIMULATION STUDIES OF MATRIX METALLOPROTEINASES MMP2 AND MMP9 AND COMPUTER AIDED DRUG DESIGNING USING PHYTOCHEMICALS AS THEIR POTENTIAL INHIBITORS

Abstract

Matrix metalloproteinases (MMPs), also designated matrixins, hydrolyze components of the extracellular matrix. These proteinases play a central role in many biological processes, such as embryogenesis, normal tissue remodeling, wound healing, and angiogenesis, and in diseases such as atheroma, arthritis, cancer, and tissue ulceration (Visse et al.,2003). MMPs, especially those capable of cleaving type IV basement membrane collagen (MMP-2 and -9) were considered to be ideal targets for drug development.Two gelatinases, MMP-2 (72-kDa gelatinase) and MMP-9 (92-kDa gelatinase), are key proteinases governing the degradation of basement membrane collagen types IV and V, as well as different types of gelatine. These two share structural and catalytic similarities; however, their gene expression is differentially regulated, partly due to the distinct structure of the regulatory elements and promoters in their genes. In contrast to MMP-9, whose expression has been implicated in renal development, macrophage differentiation, atherosclerosis, inflammation, rheumatoid arthritis, and tumor invasion, MMP-2 usually is expressed constitutively.In this study natural compounds from medicinal plants were used for drug designing for MMP2 and MMP9. Molecular dynamics simulation showed structures of MMP2 and MMP9 to be stable. Natural compound library was screened for both the targets. Screenedout ligands with low binding energy were selected. A pharmacophore model was generated from the selected ligands to ensemble of steric and electronic features that is necessary to ensure the optimal supramolecular interactions with specific biological target structures “MMP9 and MMP2” and to block their biological response. Four pharmacophore feature pattern were obtained for MMP9: (a) one hydrophobic feature (b) three hydrogen bond acceptor, for MMP2: (a) two hydrogen bond donor (b) two hydrogen bond acceptor and for MMP2 and MMP9: (a) one hydrogen bond donor (b) three hydrogen bond acceptor. Natural compounds with minimum binding energy and good druglike properties were selected. Gentiopicroside and16R,19E-isositsirikine could be predicted to be the potential drug against MMP9 and MMP2 respectively. Rhamnetin, Irilin-D and Febrifugine could be predicted to be the potential drug against both MMP9 and MMP2.