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Molecules 2018, 23(12), 3174; https://doi.org/10.3390/molecules23123174

An Application of Fit Quality to Screen MDM2/p53 Protein-Protein Interaction Inhibitors

1
Department of Medicinal Chemistry, Nanjing University of Chinese Medicine, Nanjing 210023, China
2
Department of Pharmacy, Red Stone Health Industry International Limited, NO.10 Xianlin Street, Nanjing 210038, China
3
Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH 43210, USA
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Lesheng Teng
Received: 10 November 2018 / Revised: 28 November 2018 / Accepted: 30 November 2018 / Published: 1 December 2018
(This article belongs to the Special Issue Application of Novel Method in Pharmaceutical Study)
Full-Text   |   PDF [5321 KB, uploaded 6 December 2018]   |  

Abstract

The judicious application of ligand or binding efficiency (LE) metrics, which quantify the molecular properties required to obtain binding affinity for a drug target, is gaining traction in the selection and optimization of fragments, hits and leads. Here we report for the first time the use of LE based metric, fit quality (FQ), in virtual screening (VS) of MDM2/p53 protein-protein interaction inhibitors (PPIIs). Firstly, a Receptor-Ligand pharmacophore model was constructed on multiple MDM2/ligand complex structures to screen the library. The enrichment factor (EF) for screening was calculated based on a decoy set to define the screening threshold. Finally, 1% of the library, 335 compounds, were screened and re-filtered with the FQ metric. According to the statistical results of FQ vs. activity of 156 MDM2/p53 PPIIs extracted from literatures, the cut-off was defined as FQ = 0.8. After the second round of VS, six compounds with the FQ > 0.8 were picked out for assessing their antitumor activity. At the cellular level, the six hits exhibited a good selectivity (larger than 3) against HepG2 (wt-p53) vs. Hep3B (p53 null) cell lines. On the further study, the six hits exhibited an acceptable affinity (range of Ki from 102 to 103 nM) to MDM2 when comparing to Nutlin-3a. Based on our work, FQ based VS strategy could be applied to discover other PPIIs. View Full-Text
Keywords: virtual screening; ligand efficiency; fit quality; MDM2/p53 protein-protein interaction virtual screening; ligand efficiency; fit quality; MDM2/p53 protein-protein interaction
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Xue, X.; Bao, G.; Zhang, H.-Q.; Zhao, N.-Y.; Sun, Y.; Zhang, Y.; Wang, X.-L. An Application of Fit Quality to Screen MDM2/p53 Protein-Protein Interaction Inhibitors. Molecules 2018, 23, 3174.

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