Design of a potent anticancer lead inspired by natural products from traditional Indian medicine

Hemant Arya, C. Suresh Yadav, Shu Yu Lin, Safiulla Basha Syed, Mariasoosai Ramya Chandar Charles, Sathananthan Kannadasan, Hsing Pang Hsieh, Sorokhaibam Sureshkumar Singh, Padma Raj Gajurel, Mohane Selvaraj Coumar

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2 引文 斯高帕斯(Scopus)


Among 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.

頁(從 - 到)3563-3577
期刊Journal of Biomolecular Structure and Dynamics
出版狀態Published - 2020 八月 12

All Science Journal Classification (ASJC) codes

  • Structural Biology
  • Molecular Biology

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