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Mol Divers (2012) 16:513524 DOI 10.1007/s11030-012-9384-z
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Consensus QSAR model for identifying novel H5N1 inhibitors
Nitin Sharma Chun Wei Yap
Received: 20 April 2012 / Accepted: 25 June 2012 / Published online: 21 July 2012 Springer Science+Business Media B.V. 2012
Abstract Due to the importance of neuraminidase in the pathogenesis of inuenza virus infection, it has been regarded as the most important drug target for the treatment of inuenza. Resistance to currently available drugs and new ndings related to structure of the protein requires novel neuraminidase 1 (N1) inhibitors. In this study, a consensus QSAR model with dened applicability domain (AD) was developed using published N1 inhibitors. The consensus model was validated using an external validation set. The model achieved high sensitivity, specicity, and overall accuracy along with low false positive rate (FPR) and false discovery rate (FDR). The performance of model on the external validation set and training set were comparable, thus it was unlikely to be overtted. The low FPR and low FDR will increase its accuracy in screening large chemical libraries. Screening of ZINC library resulted in 64,772 compounds as probable N1 inhibitors, while 173,674 compounds were dened to be outside the AD of the consensus model. The advantage of the current model is that it was developed using a large and diverse dataset and has a dened AD which prevents its use on compounds that it is not capable of predicting. The consensus model developed in this study is made available via the free software, PaDEL-DDPredictor.
Keywords Applicability domain Consensus model
H5N1 In silico screening Inhibitors QSAR
Electronic supplementary material The online version of this article (doi:http://dx.doi.org/10.1007/s11030-012-9384-z
Web End =10.1007/s11030-012-9384-z ) contains supplementary material, which is available to authorized users.
N. Sharma C. W. Yap (B)
Pharmaceutical Data Exploration Laboratory, Department of Pharmacy, National University of Singapore, Block S4, 18 Science Drive 4, Singapore 117543, Singaporee-mail: [email protected]
Introduction
The avian inuenza virus type A, especially subtype H5N1, is becoming the worlds largest pandemic threat because of its high virulence and lethality in birds, rapid expansion of host reservoir, crossing of international boundaries by means of migratory birds, high mutation rate, and ability to get transmitted to human [1,2]. In recent outbreaks, avian inuenza A (H5N1) infections have caused high...