Department of Infectious Diseases, The First Affiliated Hospital of China Medical University, No. 155, Nanjing North Street, Heping District, Shenyang, 110001, Liaoning Province, China.
Clinical Center for Epilepsy, Xuanwu Hospital, 45 Changchun Street, Xicheng District, Beijing, 100037, Beijing, China.
Sci Rep. 2024 Jul 30;14(1):17597. doi: 10.1038/s41598-024-68526-0.
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.
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。虽然法尼醇 X 受体激动剂奥贝胆酸（OCA）具有良好的疗效，但应仔细考虑其安全性数据，如严重瘙痒。为了发现新的药物，我们从 ZINC15 数据库中筛选和选择可能与 FXR 呈激动剂相互作用的最佳化合物。我们利用 DS19 软件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。筛选后确定 LibDock 评分，然后检查它们的吸收、分布、代谢、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。利用分子动力学模拟评估配体-FXR 复合物在其天然环境中的稳定性。两种新型天然化合物 ZINC000013374322 和 ZINC000006036327 与 FXR 的结合亲和力更高、稳定性更好，且具有较低的啮齿动物致癌性、Ames 致突变性、无肝毒性和不抑制 CYP2D6。它们可以在环境中稳定存在，具有良好的势能，并在较低剂量下发挥药理作用。此外，与 OCA 相比，ZINC000006036327 的皮肤刺激性和致敏性潜力更低，这也表明改善皮肤瘙痒发生的可能性。ZINC000013374322 和 ZINC000006036327 被发现是 FXR 激动剂的最佳先导化合物。它们被选为 FXR 靶向药物的安全候选药物，在较低剂量下发挥相当的药理作用。
