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Int. J. Mol. Sci. 2017, 18(1), 137; doi:10.3390/ijms18010137

A Thoroughly Validated Virtual Screening Strategy for Discovery of Novel HDAC3 Inhibitors

1
State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Department of New Drug Research and Development, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
2
Molecular Modeling and Drug Discovery Core for District of Columbia Center for AIDS Research (DC CFAR), Department of Pharmaceutical Sciences, College of Pharmacy, Howard University, Washington, DC 20059, USA
These authors contributed equally to this work.
*
Author to whom correspondence should be addressed.
Academic Editor: Ge Zhang
Received: 5 December 2016 / Revised: 9 January 2017 / Accepted: 9 January 2017 / Published: 18 January 2017
(This article belongs to the Section Biochemistry, Molecular and Cellular Biology)
View Full-Text   |   Download PDF [4482 KB, uploaded 18 January 2017]   |  

Abstract

Histone deacetylase 3 (HDAC3) has been recently identified as a potential target for the treatment of cancer and other diseases, such as chronic inflammation, neurodegenerative diseases, and diabetes. Virtual screening (VS) is currently a routine technique for hit identification, but its success depends on rational development of VS strategies. To facilitate this process, we applied our previously released benchmarking dataset, i.e., MUBD-HDAC3 to the evaluation of structure-based VS (SBVS) and ligand-based VS (LBVS) combinatorial approaches. We have identified FRED (Chemgauss4) docking against a structural model of HDAC3, i.e., SAHA-3 generated by a computationally inexpensive “flexible docking”, as the best SBVS approach and a common feature pharmacophore model, i.e., Hypo1 generated by Catalyst/HipHop as the optimal model for LBVS. We then developed a pipeline that was composed of Hypo1, FRED (Chemgauss4), and SAHA-3 sequentially, and demonstrated that it was superior to other combinations in terms of ligand enrichment. In summary, we present the first highly-validated, rationally-designed VS strategy specific to HDAC3 inhibitor discovery. The constructed pipeline is publicly accessible for the scientific community to identify novel HDAC3 inhibitors in a time-efficient and cost-effective way. View Full-Text
Keywords: HDAC3 inhibitors; anti-diabetes; virtual screening; MUBD-HDACs; benchmarking calculation HDAC3 inhibitors; anti-diabetes; virtual screening; MUBD-HDACs; benchmarking calculation
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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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Hu, H.; Xia, J.; Wang, D.; Wang, X.S.; Wu, S. A Thoroughly Validated Virtual Screening Strategy for Discovery of Novel HDAC3 Inhibitors. Int. J. Mol. Sci. 2017, 18, 137.

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