Journal
JOURNAL OF MOLECULAR GRAPHICS & MODELLING
Volume 70, Issue -, Pages 129-139Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.jmgm.2016.10.003
Keywords
ADAM17; MMP; Natural molecules; Molecular dynamic simulation; Proportional odds model
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Funding
- Bio Informatics Facility, Tezpur University
- Department of Science & Technology, Govt. of India (DST-SERB) [SB/YS/LS-30/2014]
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ADAM metallopeptidase domain 17 (ADAM17) is an attractive target for the development of new anti-inflammatory drugs. We aimed to identify selective inhibitors of ADAM17 against matrix metalloproteinase enzymes (MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-13, and MMP-16) which have substantial structural similarity. Target proteins were docked with 29 anti-inflammatory natural molecule ligands and a known selective inhibitor IK682. The ligands were screened based on Lipinski rules, interaction with the ADAM17 active site cavity, and then ranked using the proportional odds model multinomial logistic regression. Silymarin was the most selective inhibitor of ADAM17 exhibiting H-bonding with Glu 406, Gly 349, Glu 398, Asn 447, Tyr 433, and Lys 432. Molecular dynamics simulations were carried out for 10 ns. The root mean square deviation (RMSD), root mean squared fluctuations (RMSF), radius of gyration (Rg), solvent accessible surface area (SASA), and H-bonding indicated the induced metastability. A comparison of the principal component analysis revealed that the silymarin complex also explored lesser region compared to 11(682 complex. A control study on ADAM17 protein (20I0) is included. These observations present silymarin (widely present in plants such as milk thistle (Silybum maianum), wild artichokes (Cynara cardunculus), turmeric (Curcuma longa) roots, coriander (Coriandrum sativum) seeds, etc.) as a promising natural template for development of ADAM17 selective drugs. (C) 2016 Elsevier Inc. All rights reserved.
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