A hybrid of artificial intelligence simple and low computational cost QSAR was used. Approximately 90 pyridinylimidazole-based drug candidates with a range of potencies against p38R MAP kinase were investigated. To obtain more flexibility and effective capability of handling and processing information about the real world, in this case, the fuzzy set theory was introduced into the QSAR. An integration of multiple linear regression and artificial neural network with adaptive neuro-fuzzy inference systems (ANFIS) was developed to predict the inhibition activity. The algorithm of ANFIS was applied to identify the suitable variables and then to find the optimal descriptors. The gradient descent with momentum backpropagation ANN was used to establish the nonlinear multivariate relationships between the chemical structural parameters and biological response. A comparison between the result of the proposed linear and nonlinear regression showed the superiority of QSAR modeling by ANFIS-ANN method over the MLR. The results demonstrated that the ANFIS could be applied successfully as a feature selection. The appearance of Diam, Homo, and LogP descriptors in the model showed the importance of the steric, electronic, and thermodynamic interactions between a drug and its target site in the distribution of a compound within a biosystem and its interaction with competing for binding sites.