Molecular Insights of 1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole as CRF-1 Receptor Antagonists: Combined QSAR, Glide Docking, Molecular Dynamics, and In-silico ADME Studies.

Abstract

Stress-dependent disorders cause severe harm to human health and trigger the risk of neurodegenerative disorder. Corticotropin-releasing factor-1 receptor was found to be a potent drug target.We evaluate the essential structural residues for pharmacophore identification through 2D and 3D QSAR analysis and identify the binding residues for a possible mechanism of CRF-1 binding with 1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole derivatives through molecular docking and molecular dynamics simulations. The best 2D QSAR model was obtained through the MLR method with an r2 value of 0.8039 and a q2 value of 0.6311. Also,a 3D QSAR model was generated through the KNN MFA method with a q2 value of 0.6013 and a q2_se value of 0.3167. Further, docking analysis revealed that residue Glu196 and Lys334 were involved in hydrogen bonding and Trp9 in Π- Π stacking. Simulation analysis proves that target protein interactions with ligands were stable, and changes were acceptable for small and globular proteins. Compound B18, a benzimidazole derivative, has an excellent binding affinity towards CRF-1 protein compared to reference molecules; hence, this compound could be a potential drug candidate for stress-dependent disorders. Based on findings, 1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazole derivatives could be a novel class of corticotropin-releasing factor 1 receptor antagonists for stress-related disorders. All benzimidazole derivatives were found to be within the acceptable range of physicochemical properties. Hence, these observations could provide valuable information for the design and development of novel and potent CRF-1 receptor antagonists.