Issue 8, 2016

Identification of novel selective MMP-9 inhibitors as potential anti-metastatic lead using structure-based hierarchical virtual screening and molecular dynamics simulation

Abstract

MMP-9 is an attractive target for the development of new anticancer drugs. In the current study, pharmacophore modeling was employed using two highly active and selective gelatinase inhibitors obtained from two X-ray crystal structures (PDB IDs: 2OVX and 2OW1) to identify novel selective MMP-9 inhibitors. The derived model was refined manually and also validated by the GH scoring method. The refined pharmacophore model, ADRR, was able to retrieve 86% of actives with a GH score of 0.774, indicating that the model was capable of retrieving the active MMP-9 inhibitors. ADRR was used to screen 2 838 166 unique structures. Hit filtration was carried out using a fitness score >1.5 and drug-likeness properties. Hierarchical clustering generates 33 clusters based on diversity. A total of 33 molecules were obtained and these molecules were taken for cross-docking studies with 5 subtype MMPs. Among 33 tested, 2 molecules, P10A-0000088030 (Lig-1) and P10A-0001383812 (Lig-2), were found to have the highest docking scores (−8.59 kcal mol−1 and −8.27 kcal mol−1) towards MMP-9 compared with the other MMPs. Further MM-GBSA analysis was performed for two hits with 5 subtype MMPs to reveal the essential features that contribute to selectivity. The results showed that van der Waals contributions play a central role in determining the selectivity of MMP-9 inhibitors. Molecular dynamics studies were carried out for total time of 330 ns to assess the stability of ligands at the active site. MD analysis showed that binding of Lig-1 with MMP-9 is stable compared to that with Lig-2. Hence, we suggest the Lig-1 compound as a good lead in designing novel potent inhibitors of MMP-9.

Graphical abstract: Identification of novel selective MMP-9 inhibitors as potential anti-metastatic lead using structure-based hierarchical virtual screening and molecular dynamics simulation

Supplementary files

Article information

Article type
Paper
Submitted
27 Jan 2016
Accepted
09 May 2016
First published
09 May 2016

Mol. BioSyst., 2016,12, 2519-2531

Identification of novel selective MMP-9 inhibitors as potential anti-metastatic lead using structure-based hierarchical virtual screening and molecular dynamics simulation

S. Kalva, N. Agrawal, A. A. Skelton and L. M. Saleena, Mol. BioSyst., 2016, 12, 2519 DOI: 10.1039/C6MB00066E

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