title: Ligand efficiency based approach for efficient virtual screening of compound libraries.
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 μM. 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 μM 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.
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan, ROC. Electronic address: yiyuke@nhri.org.tw.
authors: Yi-Yu
authors: YY
authors: Ke
authors: Centre for Bioinformatics, School of Life Sciences, Pondicherry University, Kalapet, Puducherry 605014, India.
authors: Mohane Selvaraj
authors: MS
authors: Coumar
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan, ROC.
authors: Hui-Yi
authors: HY
authors: Shiao
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan, ROC.
authors: Wen-Chieh
authors: WC
authors: Wang
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan, ROC.
authors: Chieh-Wen
authors: CW
authors: Chen
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan, ROC.
authors: Jen-Shin
authors: JS
authors: Song
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan, ROC.
authors: Chun-Hwa
authors: CH
authors: Chen
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan, ROC.
authors: Wen-Hsing
authors: WH
authors: Lin
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan, ROC.
authors: Szu-Huei
authors: SH
authors: Wu
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan, ROC.
authors: John T A
authors: JT
authors: Hsu
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan, ROC.
authors: Chung-Ming
authors: CM
authors: Chang
authors: Institute of Biotechnology and Pharmaceutical Research, National Health Research Institutes, 35 Keyan Road, Zhunan, Miaoli County 350, Taiwan, ROC. Electronic address: hphsieh@nhri.org.tw.
authors: Hsing-Pang
authors: HP
authors: Hsieh
mesh_terms: D064096:Aurora Kinase A / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D057166:High-Throughput Screening Assays; D008024:Ligands; D062105:Molecular Docking Simulation; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D011743:Pyrimidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D054852:Small Molecule Libraries / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D014584:User-Computer Interface
chemical_list: D008024:Ligands; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D054852:Small Molecule Libraries; D064096:Aurora Kinase A
keywords: Aurora kinase inhibitor; Fit quality; Ligand efficiency; Pharmacophore model; Virtual screening