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Molecules 2017, 22(6), 1029; doi:10.3390/molecules22061029

Virtual Screening against Phosphoglycerate Kinase 1 in Quest of Novel Apoptosis 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
Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
3
Molecular Modeling and Drug Discovery Core Laboratory for District of Columbia Center for AIDS Research (DC CFAR), Department of Pharmaceutical Sciences, College of Pharmacy, Howard University, Washington, DC 20059, USA
*
Author to whom correspondence should be addressed.
Received: 20 April 2017 / Revised: 20 June 2017 / Accepted: 20 June 2017 / Published: 21 June 2017
(This article belongs to the Section Medicinal Chemistry)
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Abstract

Inhibition of apoptosis is a potential therapy to treat human diseases such as neurodegenerative disorders (e.g., Parkinson’s disease), stroke, and sepsis. Due to the lack of druggable targets, it remains a major challenge to discover apoptosis inhibitors. The recent repositioning of a marketed drug (i.e., terazosin) as an anti-apoptotic agent uncovered a novel target (i.e., human phosphoglycerate kinase 1 (hPgk1)). In this study, we developed a virtual screening (VS) pipeline based on the X-ray structure of Pgk1/terazosin complex and applied it to a screening campaign for potential anti-apoptotic agents. The hierarchical filters in the pipeline (i.e., similarity search, a pharmacophore model, a shape-based model, and molecular docking) rendered 13 potential hits from Specs chemical library. By using PC12 cells (exposed to rotenone) as a cell model for bioassay, we first identified that AK-918/42829299, AN-465/41520984, and AT-051/43421517 were able to protect PC12 cells from rotenone-induced cell death. Molecular docking suggested these hit compounds were likely to bind to hPgk1 in a similar mode to terazosin. In summary, we not only present a versatile VS pipeline for potential apoptosis inhibitors discovery, but also provide three novel-scaffold hit compounds that are worthy of further development and biological study. View Full-Text
Keywords: apoptosis; phosphoglycerate kinase 1; terazosin; virtual screening; Parkinson’s disease apoptosis; phosphoglycerate kinase 1; terazosin; virtual screening; Parkinson’s disease
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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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Xia, J.; Feng, B.; Shao, Q.; Yuan, Y.; Wang, X.S.; Chen, N.; Wu, S. Virtual Screening against Phosphoglycerate Kinase 1 in Quest of Novel Apoptosis Inhibitors. Molecules 2017, 22, 1029.

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