國家衛生研究院 NHRI:Item 3990099045/8859

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Title:	Homology modeling of DFG-in FMS-like tyrosine kinase 3 (FLT3) and structure-based virtual screening for inhibitor identification
Authors:	Ke, YY;Singh, VK;Coumar, MS;Hsu, YC;Wang, WC;Song, JS;Chen, CH;Lin, WH;Wu, SH;Hsu, JT;Shih, C;Hsieh, HP
Contributors:	Institute of Biotechnology and Pharmaceutical Research
Abstract:	The inhibition of FMS-like tyrosine kinase 3 (FLT3) activity using small-molecule inhibitors has emerged as a target-based alternative to traditional chemotherapy for the treatment of acute myeloid leukemia (AML). In this study, we report the use of structure-based virtual screening (SBVS), a computer-aided drug design technique for the identification of new chemotypes for FLT3 inhibition. For this purpose, homology modeling (HM) of the DFG-in FLT3 structure was carried using two template structures, including PDB ID: 1RJB (DFG-out FLT3 kinase domain) and PDB ID: 3LCD (DFG-in CSF-1 kinase domain). The modeled structure was able to correctly identify known DFG-in (SU11248, CEP-701, and PKC-412) and DFG-out (sorafenib, ABT-869 and AC220) FLT3 inhibitors, in docking studies. The modeled structure was then used to carry out SBVS of an HTS library of 125,000 compounds. The top scoring 97 compounds were tested for FLT3 kinase inhibition, and two hits (BPR056, IC50 = 2.3 and BPR080, IC50 = 10.7 muM) were identified. Molecular dynamics simulation and density functional theory calculation suggest that BPR056 (MW: 325.32; cLogP: 2.48) interacted with FLT3 in a stable manner and could be chemically optimized to realize a drug-like lead in the future.
Date:	2015-06-29
Relation:	Scientific Reports. 2015 Jun 29;5:Article number 11702.
Link to:	http://dx.doi.org/10.1038/srep11702
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=2045-2322&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000357027800002
Cited Times(Scopus):	http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=84934325530
Appears in Collections:	[Hsing-Pang Hsieh] Periodical Articles [Chuan Shih(2014-2017)] Periodical Articles [John Tsu-An Hsu] Periodical Articles [Wen-Chieh Wang] Periodical Articles

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