The Natural Ligand for Metalloproteinase- Multifaceted Drug Target

Abstract Metalloproteinases are a group of proteinases that extensively depend on metals for their biological activity, i.e., digesting proteins. Their role in developmental stages is indispensable. However, the same enzyme is also found to be a crucial mediator of several diseases like cancer, atheroma, arthritis, atherosclerosis, aneurysms, nephritis, tissue ulcers, fibrosis, etc. Exogenous metalloproteinases cause severe pathological effects which may even lead to mortality in humans and other higher animals. The major source of exogenous metalloproteinases is through venomous snake bites, which causes exposure of normal tissue later blood vessels to the proteinases. Though the structure and function of metalloproteinases are highly conserved, the accidental exposure causes severe irreversible damages of the exposed tissues and blood vessels which otherwise is a highly regulated process with the endogenous metalloproteinases. Hence, finding a suitable metalloproteinases inhibitor is of great biological importance in mitigating pathological effects. Batimastat is an approved drug prescribed for cancer which mediates its action by inhibiting metalloproteinases. Batimastat is a synthetic hydroxamate molecule with a simple structure that prompted the search for the existence of similar phytochemicals in plants. Computational analysis revealed interaction of Andrographis paniculata phytochemicals with the M domain of snake venom metalloproteinase active site amino acid residues namely ASN203, ARG293, PHE203, LEU206, LYS199, and ALA122 similar to that of the reference compound batimastat. 14-acetylandrographolide, 14-deoxy-11,12 didehydroandrographolide, Andrograpanin, Isoandrographolide, and 14-deoxy-11-oxoandrographolide found to show maximum effectiveness against the metalloproteinase. Results of the current study show a possibility of developing potent drug targeting metalloproteinases from plants source.