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Scaffold Based Screening and Molecular Dynamics Simulation Study Identifies Two Structurally Related Phenolic Compound as Potent MMP1 Inhibitors.

Author(s):

Swagata Patra, Parameswaran Saravanan, Bhaskar Das, Venkatesan Subramanian and Sanjukta Patra*   Pages 1 - 38 ( 38 )

Abstract:


Background: Matrix metalloproteinase 1 is zinc dependent endopeptidase playing important role in the controlled breakdown of extracellular matrix in normal physiological condition resulting in maintenance of homeostasis. Dysregulation of MMP1 leads to progression of various pathological conditions as cancer, rheumatoid arthritis, cardiovascular disease, skin damage and fibrotic disorder. Thus, MMP1 inhibition may prove to be potential drug target. Many synthetic MMP1 inhibitors are available, but its clinical applicability is hindered by lack of substrate specificity. Hence, inhibitors from natural products have gained widespread attention.

Objective: The present study attempts screening of novel MMP1 inhibitors from ZINC database based on experimentally reported natural inhibitors of MMP1 as scaffold.

Method: Molecular docking study was performed with 19 experimentally reported natural inhibitors spanning across nine different classes followed by virtual screening using the selected compounds. The selected compounds were subjected to molecular dynamics simulation.

Results: Twenty compounds were screened with a cut-off of -9.0 kcal/mol of predicted free energy of binding, which further converged to 6 hits after docking studies. After comparing the docking result of 6 screened hits, two best compounds were selected. ZINC02436922 had the best interaction with six hydrogen bond formation to a relatively confined region in the S1’site of MMP1 and -10.01 kcal/mol of predicted free energy of binding. ZINC03075557 was the second-best compound with -9.57 kcal/mol predicted binding free energy. Molecular dynamics simulation of ZINC02436922 and ZINC03075557 corroborates docking study.

Conclusion: This study brings out phenolic compounds ZINC02436922 and ZINC03075557 as potential MMP1 inhibitors.

Keywords:

MMP1, Natural inhibitor, Virtual screening, Molecular docking, Molecular Dynamics simulation, Phenolics.

Affiliation:

Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, Centre for the Environment, Indian Institute of Technology Guwahati, Guwahati, Assam, Chemical Laboratory, CSIR-Central Leather Research Institute, Adyar, Chennai, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam



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