基于计算机辅助药物设计从中药天然产物库中挖掘儿童神经母细胞瘤靶点极光激酶A抑制剂  

Computer-aided Drug Design:Mining Neuroblastoma Targets in Children Aurora A Kinase Inhibitors from a Natural Product Library of Traditional Chinese Medicine

作　　者：刘天一 胡清洋 东雪 辛彬 王欢欢 李中 LIU Tianyi;HU Qingyang;DONG Xue;XIN Bin;WANG Huanhuan;LI Zhong(Department of Pharmaceutics,Dalian Women and Children’s Medical Group,Dalian 116012,China;College of Pharmacy,Dalian Medical University,Dalian 116044,China)

机构地区：[1]大连市妇女儿童医疗中心(集团)药剂科,辽宁大连116012 [2]大连医科大学药学院,辽宁大连116044

出　　处：《中国现代应用药学》2023年第22期3104-3116,共13页Chinese Journal of Modern Applied Pharmacy

基　　金：大连市医学科学研究计划项目(22Z12007)。

摘　　要：目的利用计算机辅助药物设计技术从中药天然产物库中挖掘极光激酶A(Aurora A kinase,AURKA)抑制剂。方法搭建类药性筛选、药动学预测、分子对接、分子动力学(molecular dynamics,MD)模拟于一体的药物筛选平台,从中药化合物数据库中挖掘AURKA抑制剂并通过MD模拟进行验证。结果采用计算机辅助药物设计方法从Bai-TCM数据库6220种中草药的47696种中药天然化合物中筛选出5种能与AURKA结合的化合物。经MD模拟验证发现Compound X能够在AURKA抑制活性口袋中形成稳定的受体-配体二元复合物,在Compound X存在的情况下,AURKA-MYCN复合物的稳定性明显降低。结论结合多种虚拟筛选技术从中药天然产物数据库发现神经母细胞瘤治疗靶点MYCN的AURKA抑制剂Compound X。OBJECTIVE Neuroblastoma(NB)is a prevailing pediatric extracranial solid tumor that accounts for 10%−15%of all childhood cancer-related fatalities.Despite significant strides made in NB therapy through multimodal approaches,the survival rate of high-risk NB patients remains at approximately 50%.Consequently,there is an urgent need to identify novel molecular targets for NB treatment.Recent studies have shown that MYCN oncogene amplification is present in about 25%of NB cases and is a crucial determinant of poor prognosis for high-risk NB patients.Since MYC family proteins,including MYCN,are inherently disordered proteins,MYCN lacks a defined ligand binding site along with a large protein-protein interaction surface.Current treatment approaches for MYCN-amplified NB patients do not include direct targeting of MYCN itself,since the absence of a“drugable”pocket renders it challenging.Notably,no direct MYC-targeting drugs are currently available.There is an existing association between Aurora A kinase(AURKA)and MYCN,whereby they form a complex to fortify MYCN stability.However,MYCN is inherently unstable,with a half-life of only 30 min,but AURKA intervenes by facilitating its stability through a direct protein-protein interaction,hence protecting it from proteasomal degradation.This interaction potentially augments tumor cell proliferation and invasiveness.Notably,AURKA has been verified as a transcriptional target of MYCN.The present study endeavors to employ computer-aided drug design technology to probe AURKA inhibitors discerned from a natural product library of traditional Chinese medicine(TCM),thereby identifying a novel drug for treating NB.METHODS Collected from the YaTCM database,a total of 47696 natural compounds from TCM were subjected to preprocessing including protonation,deionization,hydrogenation,stereoisomerism,conformation generation,and energy minimization.Of these,58048 compounds were initially screened as potential ligands for the library.Utilizing“Lipinski Ro5”and“Verber Ro3”guidelin

关 键 词：极光激酶A 神经母细胞瘤 计算机辅助药物设计 分子动力学模拟 分子对接 

分 类 号：R965.2[医药卫生—药理学]