MOLECULAR DYNAMICS STUDIES OF FULL HUMAN MATRIX METALLOPROTEINASE 9 LIGANDED WITH N-HYDROXY-2-[(4-PHENYLPHENYL) SULFONYL-PROPAN-2-YLOXYAMINO] ACETAMIDE

Roy Gunawan Wicaksono,Maywan Hariono,Enade Perdana Istyastono

doi:10.24071/jpsc.001970

Roy Gunawan Wicaksono, Maywan Hariono + Show 1 more

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https://doi.org/10.24071/jpsc.001970

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Abstract

The research presented in this article aimed to provide a full quarternary structure of human matrix metalloproteinase 9 (MMP9) enzyme with a ligand in the catalytic site for structure-based virtual screening. The enzyme plays an important role in wound healing of diabetic foot ulcer. By employing the primary structure of the enzyme obtained from UniProt database (UniProt:P14780), the theoretical structure of full apoenzyme of the human MMP9 (PDB:1LKG), the crystal structures of the catalytic domain (PDB:4H3X) and the hemopexin domain (PDB:1ITV) of the human MMP9, homology modeling studies have been performed. The ligand N-2-(biphenyl-4-yl-sulfonyl)-N-2-(isopropyloxy)-acetohydroxamic acid (CC27) or N-hydroxy-2-[(4-phenylphenyl)sulfonyl-propan-2-yloxyamino]acetamide (IUPAC version) from PDB:4H3X was embedded in the catalytic site of the enzyme. The modeling made use of the modules of homology modeling in YASARA structure. Subsequently, molecular dynamics (MD) simulations in YASARA structure were performed to examine the stability of the enzyme. The homology model was found stable after 5.05 ns and the lowest energy of the model was found at the 6.40 ns of the MD production run. This lowest energy snapshot was then energetically minimized and analyzed for its applicability for virtual screening. This optimized model was then stored in Mendeley Data (DOI: 10.17632/4gsb4p75gz.1).

Highlights

Enzyme matrix metalloproteinase 9(MMP9) becomes a molecular target of interest in the discovery of therapeutic agents for a diabetic foot ulcers and cancer (Hariono et al, 2018)
The research presented in this article aimed to publicly provide a full quarternary structure of human MMP9 with a relevant ligand in the catalytic site to be used further in drug discovery for diabetic wound healing
The result of the homology modeling is available in 3 formats: YASARA scene, YASARA object, and Protein Data Bank (PDB) file

Summary

Introduction

Enzyme matrix metalloproteinase 9(MMP9) becomes a molecular target of interest in the discovery of therapeutic agents for a diabetic foot ulcers and cancer (Hariono et al, 2018). The enzyme comprises a catalytic domain and a hemopexin-like domain, which have different roles (Roeb et al, 2002). The catalytic domain degrades the damaged matrix membrane in the wound healing processes (Vandooren et al, 2017). Uncontrolled enzyme activity causes the membrane degradation and formation balance disruption in the wound healing processes (Ayuk et al, 2016). Inhibitors in the catalytic domain are required to control the balance (Jones et al, 2019). Existed in the same MMP9 enzyme, the hemopexin domain has a different role (Dufour et al, 2010). The growth of cancer cells could, be inhibited by inhibitors for the hemopexin domain (Alford et al, 2017)

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