PDF(Pubmed)
Abstract：
The farnesoid X receptor (FXR) is a crucial therapeutic target for treating non-alcoholic steatohepatitis (NASH). Although obeticholic acid (OCA) as a FXR agonist presents good efficacy, the safety data such as severe pruritus should be carefully considered. To discover new medications, we screen and choose the optimal compounds from ZINC15 database that may agonistically interact with FXR. We utilized the DS19 software to assist us in conducting the computer-aided structure based virtual screening to discover potential FXR agonists. After LibDock scores were determined by screening, their absorption, distribution, metabolism, excretion and toxicity predictions were examined. To determine the binding affinity between the chosen drugs and FXR, molecule docking was utilized. Molecular dynamics simulation was utilized to evaluate the stabilization of the ligand-FXR complex in its native environment. Higher binding affinity and stability with FXR were observed for ZINC000013374322 and ZINC000006036327, as two novel natural compounds, with lower rodent carcinogenicity, Ames mutagenicity, no hepatotoxicity and non-inhibitors of CYP2D6. They could stably exist in the environment, possess favorable potential energy and exert pharmacological effects at lower doses. Furthermore, ZINC000006036327 had lower skin irritancy and sensitization potential compared to OCA, also suggest the possibility of improved skin itching occurrence. ZINC000013374322 and ZINC000006036327 were found to be the best leading compounds to be FXR agonists. They are chosen as safe candidates for FXR target medicine, which play comparable pharmacological effects at lower doses.
摘要：
法尼醇X受体(FXR)是治疗非酒精性脂肪性肝炎(NASH)的重要治疗靶点。尽管奥贝胆酸（OCA）作为FXR激动剂具有良好的疗效，应仔细考虑严重瘙痒等安全性数据.为了发现新的药物，我们从ZINC15数据库中筛选并选择可能与FXR剧烈相互作用的最佳化合物。我们利用DS19软件来协助我们进行基于计算机辅助结构的虚拟筛选以发现潜在的FXR激动剂。通过筛选确定LibDock评分后，他们的吸收，分布，新陈代谢，检查了排泄和毒性预测。为了确定所选药物与FXR之间的结合亲和力，利用分子对接。分子动力学模拟用于评估配体-FXR复合物在其天然环境中的稳定性。对于两种新型天然化合物ZINC000013374322和ZINC000006036327，观察到与FXR的更高的结合亲和力和稳定性，具有较低的啮齿动物致癌性，Ames致突变性,没有肝毒性和CYP2D6的非抑制剂。它们可以稳定地存在于环境中，具有有利的势能并在较低剂量下发挥药理作用。此外，与OCA相比，ZINC000006036327具有较低的皮肤刺激性和致敏潜力，还提示改善皮肤瘙痒发生的可能性。发现ZINC000013374322和ZINC000006036327是作为FXR激动剂的最佳先导化合物。他们被选为FXR目标药物的安全候选人，在较低剂量下发挥相当的药理作用。
