Journal of Chinese Pharmaceutical Sciences ›› 2015, Vol. 24 ›› Issue (9): 572-580.DOI: 10.5246/jcps.2015.09.073

• Original articles • Previous Articles     Next Articles

Comparison and discovery of potential non-covalent CD38 inhibitors by virtual screening strategy based on natural substrates and known inhibitors

Xiwen Xue1, Wenjie Zhu2, Liangren Zhang1, Yongjuan Zhao2, Zhenming Liu1*   

  1. 1. State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing 100191, China
    2. Shenzhen Graduate School, Peking University, Shenzhen, Guangdong 518055, China
  • Received:2015-05-18 Revised:2015-06-10 Online:2015-09-18 Published:2015-06-18
  • Contact: Tel.: 86-10-82805514, Fax: 86-10-82802724, E-mail:
  • Supported by:
    National Natural Science Foundation of China (Grant No. 21272017 and 81172917).


As a type II or III transmembrane glycoprotein, human CD38 is ubiquitously expressed in all mammalian tissues. CD38 is a multi-functional enzyme and a member of the ADP-ribosyl cyclase family, and it catalyzes nicotinamide adenine dinucleotide (NAD+) and nicotinamide adenine dinucleotide phosphate (NADP+) to two distinct Ca2+ messengers as follows: cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP), respectively. Moreover, both cADPR and NAADP mediate mobilization of intracellular Ca2+ targeting endoplasmic stores and the lysosomes, respectively. In this study, we combined ligand-based and structure-based virtual screening strategies to compare the inhibitor discovery efficacy based on natural substrates and the known inhibitors. The similarity queries towards SPECS database were carried out using ROCS and EON modules of OpenEye software. The hits were further docked to CD38 using AutoDock 4.05 program. In addition, ADME studies were also processed considering solubility in water and membrane permeability. Finally, we identified 17 compounds-based on natural substrates and 10 compounds based on known inhibitor models. The results showed that the known inhibitor H2-based model was more efficient in virtual screening of CD38 non-covalent inhibitors.

Key words: CD38, Virtual screening, Natural substrate, Non-covalent inhibitor

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