國家衛生研究院 NHRI:Item 3990099045/12152

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Title:	Design of a potent anticancer lead inspired by natural products from traditional Indian medicine
Authors:	Arya, H;Yadav, CS;Lin, SY;Syed, SB;Charles, MRC;Kannadasan, S;Hsieh, HP;Singh, SS;Gajurel, PR;Coumar, MS
Contributors:	Institute of Biotechnology and Pharmaceutical Research
Abstract:	Among the plant constituents of Clerodendrum colebrookianum Walp., acteoside, martinoside, and osmanthuside beta 6 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 mu M), which has >3-fold higher antiproliferative activity than fasudil (IC50 = 87 mu M) 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
Date:	2020-08
Relation:	Journal of Biomolecular Structure and Dynamics. 2020 Aug;38(12):3563-3577.
Link to:	http://dx.doi.org/10.1080/07391102.2019.1664326
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0739-1102&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000486773600001
Cited Times(Scopus):	https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85073937836
Appears in Collections:	[Hsing-Pang Hsieh] Periodical Articles [Shu-Yu Lin] Periodical Articles

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