The Study Of Homology Modeling And Investigating The Binding Mechanism Of Adrenocorticotropic Hormone-releasing Factor Ⅰ Receptor

Corticotropin releasing factor (CRF) is an important neuroendocrine peptide andan important neurotransmitter of the central nervous system. Human body secretsCRF from the hypothalamic paraventricular nucleus cells because of the stimulationof stress and then promotes the pituitary cells to secrete adrenocorticotropic hormone(ACTH) into the bloodstream circulatory system, thereby it makes the secreting ofcorticosteroids from the adrenal cortex. And the ending is leading to a series ofphysiological functions and behavioral responses. Thus, as a potential target fortreatment of neuropsychiatric diseases, drug design and synthesis of the CRF1receptor antagonist has become very hot.Through homology modeling, molecular docking and molecular dynamicsmethods, this topic to investigate the mechanism of the interaction of the CRF1receptor protein and inhibit molecules.This article has explored some applications of computer-aided drug designmethods in CRF1receptor. MODELLER9V7software, which have been reportedrecetently, has been use to build three-dimensional crystal structures of CRF1receptorfrom the crystal structures of the themples of three GPCR family proteins. And thenwe use the evaluation software to get the most reasonable CRF1receptorthree-dimensional structure.14inhibitors of different types are sent into the CRF1receptor structure by the molecular docking software AutoDock v4.0in order to findout the combination mechanisms. The results obtained indicates the binding modebetween the CRF1receptor and the inhibitors, while the inhibitors is mainlycomposed of three parts (P1, P2and P3). The activity values of14inhibitors obtainedand their binding energy is between a good linear relationship (R2=0.806). At thesame time, the results also show that the CRF1receptor’s C287, F289, F359, F373,I374and other residues play a key role in the combined mode. The moleculardynamics verifies that inhibitors I1-I14make strong and reasonable conformation,which also proves the molecular dockings before are reasonable.The binding-model studies of CRF1receptor and its inhibitors provide atheoretical reference for the further research of finding CRF1receptor inhibitors. Tothe design of the new structures of the CRF1receptor inhibitors, they are also of great significance.