Targeting the difficult-to-drug CD71 and MYCN with gambogic acid and vorinostat an a class of neuroblastomas

摘要

Diffuse brain gliomas are most common type of primary brain tumors and associated with poor prognosis. In this study, we aimed to reveal impact of IDH1 mutation status on long term patient prognosis. The human Cannabinoid receptor 1 (CB1) receptor which is acti- vated by endocannabinoids is expressed in the peripheral nervous system and central nervous system. And this endocannabinoid sys- tem also related to many health conditions and diseases, such as anxiety, motor control, drug behavioral addictions. Therefore, CB1 is a promising therapeutic target for a variety of disorders. Dis- tinct efficacy profiles showed different therapeutic effects on CB1 dependent on three classes of ligands: agonists, antagonists, and inverse agonists. To discriminate the distinct efficacy profiles of the ligands, we carried out molecular dynamics (MD) simulations to identify the dynamic behaviors of inactive and active conforma- tions of CB1 structures with the ligands. In additions, the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method was applied to analyze the binding free energy decompositions of the CB1-ligand complexes. With these two methods, we found the possibility that the three classes of ligands can be discriminated. Our findings shed light on the understanding of different efficacy profiles of ligands by analyzing the structural behaviors of intact.