2. Academic Validation
  3. Virtual Screening against Phosphoglycerate Kinase 1 in Quest of Novel Apoptosis Inhibitors

Virtual Screening against Phosphoglycerate Kinase 1 in Quest of Novel Apoptosis Inhibitors

  • Molecules. 2017 Jun 21;22(6):1029. doi: 10.3390/molecules22061029.
Jie Xia 1,  Bo Feng 2,  Qianhang Shao 3,  Yuhe Yuan 4,  Xiang Simon Wang 5,  Naihong Chen 6,  Song Wu 7
Affiliations

Affiliations

  • 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. jiexia@imm.ac.cn.
  • 2 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. fengbo@imm.ac.cn.
  • 3 Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. shaoqianhang@imm.ac.cn.
  • 4 Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. yuanyuhe@imm.ac.cn.
  • 5 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. x.simon.wang@gmail.com.
  • 6 Department of Pharmacology, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China. chennh@imm.ac.cn.
  • 7 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. ws@imm.ac.cn.
PMID: 28635653 DOI: 10.3390/molecules22061029
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.

Keywords

Parkinson’s disease; apoptosis; phosphoglycerate kinase 1; terazosin; virtual screening.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z