整合素α_vβ_3受体配体的计算机辅助设计  

The application of computer aided drug design in the development of integrinα_vβ_3 ligands

作　　者：张春丽[1] 

机构地区：[1]北京大学第一医院,北京100034

出　　处：《计算机与应用化学》2011年第6期661-665,共5页Computers and Applied Chemistry

基　　金：放射性药物教育部重点实验室开放基金资助项目;(编号:0707)

摘　　要：肿瘤血管生成是肿瘤生长、浸润和转移过程中不可缺少的生物过程,整合素α_vβ_3对肿瘤血管生成起着重要作用。研发具有高亲和力和高特异性的整合素α_vβ_3受体配体在针对肿瘤血管生成进行靶向诊断与靶向治疗中具有重要意义。计算机辅助药物设计技术的问世,极大地推动了新型整合素α_vβ_3受体配体的研发。整合素α_vβ_3受体细胞外区X射线晶体衍射结构的获得为针对整合素α_vβ_3受体的药物设计奠定了基础。计算机辅助药物设计包括基于分子对接法(Docking)的直接药物设计和基于药效团的间接药物设计,Docking可预测配体-蛋白的相互作用、对受体-配体结合进行三维构效关系研究、设计具有高亲和力与选择性的新型配体。通过将小分子数据库与α_vβ_3受体(PDB号为1L5G)进行对接,筛选出具有较高亲和力的α_vβ_3受体拮抗剂-3(3-吡啶基)-3-[4-[2-(5,6,7,8-四氢[1,8]萘啶-2)乙基]吲哚-1]丙酸和3,4-二氯苯基双胍,后者与目前已知的配体具有不同的受体结合模式。在间接药物设计中,提出了以Arg的带正电荷的侧链、Asp的带负电荷的侧链和Gly的疏水基团为药效团特征的三点药效团模型和以氢键供体、氢键受体、芳环作用、疏水作用和负离子中心为特征的药效团模型,筛选出具有nM级及低于nM级亲和力的化合物。近年来,随着计算机技术的飞速发展,预测精确度更高的软件以及更为合理的设计方法,如5D-QSAR及6D-QSAR,正在研究中,这必将使药物设计更为准确、有效。本文对计算机辅助药物设计领域的研究现状和取得的进展进行综述。Tumor angiogenesis is a indispensable biological process in tumor growth,invasion and metastasis,and integrinαvβ3 play an important role in tumor angiogenesis.Development of integrinαvβ3 ligands with high affinity and high specificity has great value in the tumor diagnosis and therapy by targeting to tumor neovessels.The technology of computer aided drug design（CADD）greatly promotes the researches on the novel integrinαvβ3 ligands.The discovery of crystal structure of the extracellular segment of integrinαvβ3 provided the structural basis for the design ofαvβ3 ligands.CADD includes direct drug design and indirect drug design.The direct drug design is the structure-based drug design by docking procedure which can be used to predict ligand-protein interactions,investigate the three-dimensional structure-activity relationship and design novel potent and highly selective ligands.A number of novel ligands such as 3-（3-pyridyl）-3-[4-[2-（5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl）ethyl]indol-1-yl] propionic acid and 3,4-dichloro-phenylbiguanide has been developed which either has high affinity toαvβ3 receptor or binds the receptor in a different mode from the known ligands through docking the small molecule database to integrinαvβ3 receptor（PDB entry,1L5G）.The indirect drug design is pharmacophore-based design.3-point pharmacophore with charge-charge interactions of Arg,Asp,and hydrophobicity of Gly in the RGD sequence as key features and five-featured pharmacophore with H-bond donor（HBD）,H-bond acceptor（HBA）,ring aromatic（HYR）,hydrophobic（HYA）,and negatively ionizable（NI）feature were proposed.Novel compounds with nanomolar to subnanomolar binding affinity have been developed through the pharmacophore screening of a database of small-molecule compounds.Recently,with the development of computer science,more predictive accuracy softwares and more reasonable methods such as 5D-QSAR and 6D-QSAR are being under investigating,which will significant improve the binding prediction

关 键 词：整合素 αvβ3受体 肿瘤血管生成 计算机辅助药物设计 

分 类 号：R730.1[医药卫生—肿瘤] R914.2[医药卫生—临床医学]