Discovery of Novel NAMPT Inhibitors Based on Pharmacophore Modeling and Virtual Screening Techniques

Author(s): Qianying Yi, Lu Zhou, Xin Shao, Taijin Wang, Guangkai Bao, Huanhuan Shi, Suwen Zhou, Xiaoli Li, Yahui Tian.

Journal Name: Combinatorial Chemistry & High Throughput Screening

Volume 17 , Issue 10 , 2014

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Abstract:

Nicotinamide phosphoribosyltransferase (NAMPT), an enzyme taking part in main NAD biosynthetic pathway, is an attractive target for anticancer therapy. The purpose of our study is to find novel NAMPT inhibitors based on in silico drug discovery means including the generation of 3D-QSAR models, and virtual screening techniques. Firstly, ten pharmacophore models were generated by Catalyst/HypoGen algorithm. Hypo1 with high correl value (0.96), large Δcost (77.77), and low root mean square deviation (0.81), featured by four chemical features was selected as the best one. Subsequently, Hypo1 was validated through test set prediction and Fischer’s randomization methodologies. Then we screened some public compound libraries (Asinex, Ibscreen and Natural products database) using Hypo1 for a 3D query. The screened hits were further refined by Lipinski’s rule of five, ADMET properties as well as molecular docking studies. Finally, six molecules with diverse scaffolds exhibited the right pharmacophore features and good binding modes between the receptor and ligands, and were selected as possible candidates against NAMPT for further study.

Keywords: 3D QSAR models, Catalyst/HypoGen, molecular docking, NAMPT, virtual screening.

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Article Details

VOLUME: 17
ISSUE: 10
Year: 2014
Page: [868 - 878]
Pages: 11
DOI: 10.2174/1386207317666141121124139
Price: $58

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