Study on the antagonists for the orphan G protein-coupled receptor GPR55 by quantitative structure–activity relationship

• We established several reliable models by MLR, SMILES-based and 3D-QSAR.
• Several structural features that may help to design potent inhibitors were discussed.
• Various validation methods for the test set were used to validate established models.
• Six new potential inhibitors with higher predicted activities were designed.
• Twenty-eight compounds without clear activities were tested by four models.

The orphan G protein-coupled receptor GPR55 has been proposed as a new potential drug target for the treatment of diabetes, Parkinson's disease, neuropathic pain, and cancer. Coumarin and 8-amido-chromen-4-one-2-carboxylic acid derivatives were identified as novel antagonists for GPR55. In this study, we established reliable models and explored the valuable information by quantitative structure–activity relationship (QSAR). Firstly, we obtained a quite reliable multiple linear regression (MLR) model with correlation coefficient (R2) of 0.8204 for the training set, and R2 of 0.7770 for the test set. Next, we built a better model with R2 of 0.8763 for the training set, and R2 of 0.8179 for the test set based on the simplified molecular input line entry system (SMILES). Lastly, we established dependable comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) models. Then we validated these models' predictive ability using various validation methods for the test set. Besides, we designed and confirmed six new potential inhibitors with higher predicted activities and tested twenty-eight compounds without clear activities by the established models. The results obtained from molecular modeling not only provide models to predict the activities of inhibitors but also lead to a better understanding of the essential features that should be considered when designing novel inhibitors with desired activities.