酮醇酸还原异构酶(KARI)与其抑制剂间相互作用的分子模拟研究

采用MCCE, Autodock及密度泛函方法对酮醇酸还原异构酶(KARI)与其抑制剂间相互作用进行了研究. 计算结果表明, KARI活性位点中的Mg^2＋在活性位点残基的离子化状态、活性位点的静电性质以及与抑制剂结合等方面起重要的作用; 同时, 抑制剂在结合方式、前线轨道布居及静电势等方面与酶促反应中间体(HOIV)具有一定程度的相似性; 可电离的羧基是当前发现的靶向KARI抑制剂一个重要的结构特征, 进一步推广可认为潜在的抑制剂应该拥有可电离成负电荷的功能团. 在药物设计中考虑到以上结论, 将有利于发现和改造靶向KARI的抑制剂.

Molecular Simulation Studies of Interactions between Ketol-acid Reductoisomerase and Its Inhibitors

The interactions between ketol-acid reductoisomerase(KARI)and its inhibitors were studied by a series of molecular simulation techniques such as MCCE,Autodock and density functional theory.The calculated results indicated that Mg2 ions at the active site played important roles in determining the ioni-zation states of the residues at the active site,electrostatic properties of the active site and ligand binding.The potential inhibitors are similar in the binding mode of KARI,population of the frontier orbitals and electrostatic potentials.The results also identified the ionizable carboxyl groups as a key structural feature for inhibition of KARI.Based on this conclusion,it was further deduced that the potential inhibitors proba-bly had an ionizable group that could release proton and be negatively charged.The conclusions of present study will provide valuable information for designing further potent KARI inhibitors prior to their synthesis.