國家衛生研究院 NHRI:Item 3990099045/8601
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    题名: Efficient virtual screening using ligand efficiency based approach
    作者: Hsieh, HP;Ke, YY;Coumar, MS;Lin, WH;Wang, WC;Shiao, HY;Hsu, TAJ
    贡献者: Institute of Biotechnology and Pharmaceutical Research
    摘要: Efficiency virtual high-throughput screening (vHTS) is an important manner to screen hits from massive database. We present the application of combining the ligand-based, structure-based and fragment-based screening for a novel VS protocol to screen in-house library of 125,000 compounds for aurora kinase A inhibitors. First, 20 known aurora kinase inhibitors were docked to aurora kinase A crystal structure (PDB ID: 2W1C) and the docked ligand conformations were used to create pharmacophore model (PH).The PH model was used to screen the database compounds, and rank (PH rank) them based on the predicted IC50 values. Next, a fragment-based ligand efficiency (LE_Scale) function was derived from 294 known aurora kinase inhibitors. Using fit quality (FQ = LE/LE_Scale) score derived from 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 has led to the identification of 7 novel hits, with compound BPR05 showing aurora kinase A IC50 = 1.65 mM. Furthermore, synthesis and testing BPR05 against a panel of 31 kinase reveals that it is selective towards aurora kinase A & B, with < 50% inhibition for other kinases at 10 μM concentrations and is a suitable lead for further development. The LE based approach in the VS protocol not only helped in identifying a novel aurora kinase inhibitor BPR05 , but also increased the hit rate of VS protocol considerably by improving the Enrichment factor (EF) for Fit quality based screening (PH_FQ screening, EF = 828), compared to pharmacophore based screening (PH screening, EF = 237) alone, and the Goodness of fit score (GF) from 0.24 (PH screening) to 0.35. We suggest that this LE based application described here could be incorporated in the VS protocols for other targets to improve the hit rates.
    日期: 2014-03
    關聯: Abstracts of Papers - American Chemical Society. 2014 Mar;247:Article number 55-MEDI.
    Link to: http://acselb-529643017.us-west-2.elb.amazonaws.com/chem/247nm/program/view.php
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000348457602228
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