國家衛生研究院 NHRI:Item 3990099045/8107

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Please use this identifier to cite or link to this item: http://ir.nhri.org.tw/handle/3990099045/8107

Title:	Ligand efficiency based approach for efficient virtual screening of compound libraries
Authors:	Ke, YY;Coumar, MS;Shiao, HY;Wang, WC;Chen, CW;Song, JS;Chen, CH;Lin, WH;Wu, SH;Hsu, JT;Chang, CM;Hsieh, HP
Contributors:	Institute of Biotechnology and Pharmaceutical Research
Abstract:	Here we report for the first time the use of fit quality (FQ), a ligand efficiency (LE) based measure for virtual screening (VS) of compound libraries. The LE based VS protocol was used to screen an in-house database of 125,000 compounds to identify aurora kinase A inhibitors. First, 20 known aurora kinase inhibitors were docked to aurora kinase A crystal structure (PDB ID: 2W1C); and the conformations of docked ligand were used to create a pharmacophore (PH) model. The PH model was used to screen the database compounds, and rank (PH rank) them based on the predicted IC50 values. Next, LE_Scale, a weight-dependant LE function, was derived from 294 known aurora kinase inhibitors. Using the fit quality (FQ = LE/LE_Scale) score derived from the LE_Scale function, the database compounds were reranked (PH_FQ rank) and the top 151 (0.12% of database) compounds were assessed for aurora kinase A inhibition biochemically. This VS protocol led to the identification of 7 novel hits, with compound 5 showing aurora kinase A IC50 = 1.29 muM. Furthermore, testing of 5 against a panel of 31 kinase reveals that it is selective toward aurora kinase A & B, with <50% inhibition for other kinases at 10 muM concentrations and is a suitable candidate for further development. Incorporation of FQ score in the VS protocol not only helped identify a novel aurora kinase inhibitor, 5, but also increased the hit rate of the VS protocol by improving the enrichment factor (EF) for FQ based screening (EF = 828), compared to PH based screening (EF = 237) alone. The LE based VS protocol disclosed here could be applied to other targets for hit identification in an efficient manner.
Date:	2014-08
Relation:	European Journal of Medicinal Chemistry. 2014 Aug;83:226-235.
Link to:	http://dx.doi.org/10.1016/j.ejmech.2014.06.029
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0223-5234&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000340689600019
Cited Times(Scopus):	http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84903125391
Appears in Collections:	[Hsing-Pang Hsieh] Periodical Articles [Chung-Ming Chang] Periodical Articles [John Tsu-An Hsu] Periodical Articles [Wen-Chieh Wang] Periodical Articles

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