aⅡbb3同源模拟和环形RGD药物小分子设计

aⅡbb3 modeling simulation and Oesign of the cyclic RGD

摘要:

血小板表面的整合蛋白aⅡbb3对血栓的形成具有很重要的调控作用, aⅡbb3与纤维蛋白原上的RGD特征序列结合, 促进血小板凝集进而形成血栓。这样可以在理论上设计一个环形RGD小分子(RGD-c)与aⅡbb3蛋白结合, 阻断其与纤维蛋白原的结合位点, 进而阻断血栓形成。以糖蛋白avb3(pdb 代码 1jv2)作为模板, 利用modeller8v2软件进行同源模拟得到aⅡbb3三维模型。而小分子则以RGD序列为主, 两边各加一个氨基酸X、Y, X和Y之间用一个二硫键相连, 通过改变X和Y, 重复优化过程则可得到不同的小分子模型, 将其与aⅡbb3进行分子对接, 可以找出比较理想的XY组合, 对治疗血栓的药物设计具有重要的理论指导作用

Abstract:

Integrin aⅡbb3 of the platelet surfaces regulates the thrombosis formation. aⅡbb3 binds to the RGD sequence (Arg-Gly-Asp) of fibrinogen, promotes the platelet aggregation and finally leads to the thrombus. We obtained the three-dimensional molecular structure of aⅡbb3 using homology-modeling (modeller8v2 software), with integrin avb3 (pdb code 1JV2) as the template. Accordingly, a cyclic RGD(RGD-c) peptide was designed to bind aⅡbb3 as an antagonist and to block the formation of thrombus. We added two amino acids X, Y to both sides of RGD-c. X and Y could bind to each other by disulfide bond that finally made RGD-c a cyclic peptide. The optimum structure of RGD-c was obtained from the energetic optimization processes. All amino acids were placed at the X and Y to conduct Molecular Docking to the integrin aⅡbb3. We got the optimum structure of RGD-c by energetic optimization and the antagonistic combination analysis. The results might provide an insight into designing and screening integrin aⅡbb3 antagonists.