The Natural Ligand for Metalloproteinase-A Multifaceted Drug Target.

Saranya Shivashankar,Marimuthu Kannan Sangeetha

doi:10.1007/s12010-021-03778-4

Abstract

Metalloproteinase is one of the key components of Russell viper venom and it is the root cause of edema, blood coagulation, local tissue damage, hemorrhage, and inflammation during snakebite envenoming. Hence, finding a suitable metalloproteinase inhibitor from natural source will be of great biological importance in mitigating pathological effects. In this current study, we employed computational analysis to examine the inhibition of metalloproteinase by phytochemicals present in Andrographis paniculata. Molecular docking studies revealed interaction of A. paniculata phytochemicals with the catalytic M domain's 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 displayed high binding energy and inhibition against the metalloproteinase. Molecular dynamic simulation analysis revealed less root mean square fluctuation of amino acid residues of metalloproteinase-14-acetylandrographolide complex than metalloproteinase-Batimastat complex indicating the high stability for metalloproteinase with the phytochemical. In silico analysis of parameters like ADME properties and drug-likeness of the phytochemicals exhibited good pharmacokinetic properties. Ligand-based virtual screening of phytochemicals to identify similarity to FDA-approved drugs and identification of their possible targets were also performed. The outcome of the current study strengthens the significance of these phytochemicals as promising lead candidates for the treatment of snakebite envenomation. Moreover, the study also encourages the in vivo and in vitro evaluation of the phytochemicals to validate the computational findings.

Highlights

IntroductionMetalloproteinase are ECM (extracellular matrix) remodeling endopeptidases that can degrade the ECM component
Metalloproteinase are ECM remodeling endopeptidases that can degrade the ECM component
A 2.91 Å resolution of Snake venom metalloproteinase (SVMP) crystal structure was downloaded from the Protein Data Bank (PDB), which is managed by the Research Collaboratory for Structural Bioinformatics (RCSB), as a PDB file (PDB ID: 2E3X)

Summary

Introduction

Metalloproteinase are ECM (extracellular matrix) remodeling endopeptidases that can degrade the ECM component. Extracellular matrix degradation is a significant feature for cellular development, morphogenesis, repair, and remodeling of tissues, ever since it is associated with embryonic development and angiogenesis [1]. Metalloproteinase contains zinc and calcium that timely degrade, remodel the ECM proteins. They involve in various physiological processes regulated by cytokines, hormones, and growth factors [3]. Exogenous metalloproteinases major source of is through venomous snake bites. Snake venom metalloproteinase (SVMP), a major constituent of the viper family - especially Russell's viper (D. russelli), is peaking up to 24% of the whole venom [4]. SVMP targets capillaries and blood vessels as it selectively breaks the basement membrane’s significant bonds thereby affecting the cell membrane and endothelium interaction resulting in hemorrhage followed by cellular shock, inflammation, hypovolemia, hypotension, necrosis of tissue, and impaired regeneration of muscle tissue [5]

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