Quantitative Structure Activity Relationship (QSAR) Analysis on Substituted Pyrimidine Derivatives as Corticotropin-Releasing Factor1 Receptor Antagonists

Abstract

The corticotropin-releasing factor 1 receptor (CRF1R) antagonist is used in the treatment of patients having anxiety, depression and stress-related neurological disorders. Various pyrimidine derivatives reported as CRF1R antagonists were selected for Quantitative structure activity relationship (QSAR) analysis in order to find out quantitative relationship between biological activity and various descriptors representing physicochemical and topological properties of the molecules. Significant statistical model was generated using Multiple Linear Regression (MLR) method having higher prediction value (predicted_r2= 0.7708). The developed MLR model reveals that the descriptor 4PathCount plays most important role (59%) in determining CRF1R antagonist activity while T_C_S_7 and SsssCHE-index have 24% and 18% contribution, respectively. Absorption, distribution, metabolism, excretion, toxicity (ADMET) properties, drug likeness and drug score were also computed. The compounds 1a, 1b, 8d, and 9e have lesser hepatotoxicity and mutagenicity. The compounds 6a and 8a have good pharmacokinetics properties; lesser toxicity and good Drug likeness (DL) score, suggesting they may be drug-like compounds.