In silico identification of A1 agonists and A2a inhibitors in pain based on molecular docking strategies and dynamics simulations

Purinergic Signalling

article

Xu, Guangya¹  Zhang, Shutao¹  Zheng, Lulu¹  Hu, Zhongjiao¹  Cheng, Lijia¹  Chen, Lvlin¹  Li, Jun¹  Shi, Zheng¹ 

[1] Clinical Genetics Laboratory, Clinical Medical College & Affiliated Hospital & College of Basic Medicine & College of Food and Biological Engineering, Chengdu University;School of Pharmacy, Zunyi Medical University;Sichuan Wuyan Biotech Co. Ltd Company

关键词: Adenosine A1 receptor;    Adenosine A2a receptor;    Pain;    Potential agents;    Drug discovery;   

DOI  :  10.1007/s11302-021-09808-4

学科分类：分子生物学，细胞生物学和基因

来源: Springer

【 摘 要 】

Most recently, the adenosine is considered as one of the most promising targets for treating pain, with few side effects. It exists in the central nervous system, and plays a key role in nociceptive afferent pathway. It is reported that the A1 receptor (A1R) could inhibit Ca2+ channels to reduce the pain like analgesic mechanism of morphine. And, A2a receptor (A2aR) was reported to enhance the accumulation of AMP (cAMP) and released peptides from sensory neurons, resulting in constitutive activation of pain. Much evidence showed that A1R and A2aR could be served as the interesting targets for the treatment of pain. Herein, virtual screening was utilized to identify the small molecule compounds towards A1R and A2aR, and top six molecules were considered as candidates via amber scores. The molecular dynamic (MD) simulations and molecular mechanics/generalized born surface area (MM/GBSA) were employed to further analyze the affinity and binding stability of the six molecules towards A1R and A2aR. Moreover, energy decomposition analysis showed significant residues in A1R and A2aR, including His1383, Phe1276, and Glu1277. It provided basics for discovery of novel agonists and antagonists. Finally, the agonists of A1R (ZINC19943625, ZINC13555217, and ZINC04698406) and inhibitors of A2aR (ZINC19370372, ZINC20176051, and ZINC57263068) were successfully recognized. Taken together, our discovered small molecules may serve as the promising candidate agents for future pain research.

【 授权许可】

CC BY