Design of a potent anticancer lead inspired by natural products from traditional Indian medicine |
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Authors: | Hemant Arya C. Suresh Yadav Shu-Yu Lin Safiulla Basha Syed Mariasoosai Ramya Chandar Charles Sathananthan Kannadasan |
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Affiliation: | 1. Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, Puducherry, India;2. Department of Chemistry, School of Advanced Sciences, Vellore Institute of Technology, Vellore, Tamil Nadu, India;3. Division of Biotechnology and Pharmaceutical Research, National Health Research Institutes, Zhunan, Miaoli County, Taiwan R.O.C;4. DBT- Interdisciplinary Program in Life Sciences, Pondicherry University, Kalapet, Puducherry, India |
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Abstract: | AbstractAmong the plant constituents of Clerodendrum colebrookianum Walp., acteoside, martinoside, and osmanthuside β6 interact with ROCK, a drug target for cancer. In this study, aglycone fragments of these plant constituents (caffeic acid, ferulic acid, and p-coumaric acid) along with the homopiperazine ring of fasudil (standard ROCK inhibitor) were used to design hybrid molecules. The designed molecules interact with the key hinge region residue Met156/Met157 of ROCK I/II in a stable manner according to our docking and molecular dynamics simulations. These compounds were synthesized and tested in vitro in SW480, MDA-MB-231, and A-549 cancer cell lines. The most promising compound was chemically optimized to obtain a thiourea analog, 6a (IC50 = 25?µM), which has >3-fold higher antiproliferative activity than fasudil (IC50 = 87?µM) in SW480 cells. Treatment with this molecule also inhibits the migration of colon cancer cells and induces cell apoptosis. Further, SPR experiments suggests that the binding affinity of 6a with ROCK I protein is better than that of fasudil. Hence, the drug-like natural product analog 6a constitutes a highly promising new anticancer lead.Communicated by Ramaswamy H. Sarma |
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Keywords: | Anti-cancer clerodendrum colebrookianum Walp. docking fragment-based design molecular dynamics simulations natural product analog and ROCK |
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