Abstract
The endocannabinoid system plays an essential role in the regulation of analgesia and human immunity, and Cannabinoid Receptor 2 (CB2) has been proved to be an ideal target for the treatment of liver diseases and some cancers. In this study, we identified CB2 antagonists using a three-step “deep learning–pharmacophore–molecular docking” virtual screening approach. From the ChemDiv database (1,178,506 compounds), 15 hits were selected and tested by radioligand binding assays and cAMP functional assays. A total of 7 out of the 15 hits were found to exhibit binding affinities in the radioligand binding assays against CB2 receptor, with a pKi of 5.15–6.66, among which five compounds showed antagonistic activities with pIC50 of 5.25–6.93 in the cAMP functional assays. Among these hits, Compound 8 with the 4H-pyrido[1,2-a]pyrimidin-4-one scaffold showed the best binding affinity and antagonistic activity with a pKi of 6.66 and pIC50 of 6.93, respectively. The new scaffold could serve as a lead for further development of CB2 drugs. Additionally, we hope that the model in this study could be further utilized to identify more novel CB2 receptor antagonists, and the developed approach could also be used to design potent ligands for other therapeutic targets.
Highlights
The G-protein-coupled receptors (GPCRs), containing about 800 members, are the largest membrane protein family known in the human body [1]
We identified Cannabinoid Receptor 2 (CB2) receptor antagonists using a developed multi-step virtual screening strategy integrating deep learning, pharmacophore, and molecular docking methods [22] (a “deep learning–pharmacophore–molecular docking” virtual screening workflow)
In order to find a batch size that maximizes the performance of the DNN model, we constructed seven CB2-receptor-antagonist DNN classification models with batch sizes ranging from 50 to 350 with an interval of 50, which were tested on the test set
Summary
The G-protein-coupled receptors (GPCRs), containing about 800 members, are the largest membrane protein family known in the human body [1]. About one-third of the marketed drugs exert their effects by binding to GPCRs and modifying their intracellular signals [2]. The CB1 receptor is coupled to several calcium and potassium channels via G protein [6]. These receptors are widely distributed in the central and peripheral neurons, and inhibition of neurotransmitter release is their main function. The expression of the CB1 receptor is low, both receptors exert a wide range of immune functions, such as regulating the release of cytokines [7]. The CB2 receptor is slightly expressed in the central nervous system [8]
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