Maitarad Phornphimon, Saparpakorn Patchreenart, Hannongbua Supa, Kamchonwongpaisan Sumalee, Tarnchompoo Bongkoch, Yuthavong Yongyuth
Department of Chemistry, Faculty of Science, Kasetsart University, Bangkok, Thailand.
J Enzyme Inhib Med Chem. 2009 Apr;24(2):471-9. doi: 10.1080/14756360802201223.
Comparative molecular field analysis (CoMFA) was performed on twenty-three pyrimethamine (pyr) derivatives active against quadruple mutant type (Asn51Ile, Cys59Arg, Ser108Asn, Ile164Leu) dihydrofolate reductase of Plasmodium falcipaarum (PfDHFR). The represented CoMFA models were evaluated based on the various three different probe atoms, C(sp3) (+1), O(sp3) (-1) and H (+1), resulting in the best model with combined three types of probe atoms. The statistical results were r(2)(cv) = 0.702, S(press) = 0.608, r(2)(nv) = 0.980, s = 0.156, and r(2)(test-set) = 0.698 which can explain steric contribution of about 50%. In addition, an understanding of particular interaction energy between inhibitor and surrounding residues in the binding pocket was performed by using MP2/6-31G(d,p) quantum chemical calculations. The obtained results clearly demonstrate that Asn108 is the cause of pyr resistance with the highest repulsive interaction energy. Therefore, CoMFA and particular interaction energy analyses can be useful for identifying the structural features of potent pyr derivatives active against quadruple mutant type PfDHFR.
对23种对恶性疟原虫（PfDHFR）四重突变型（Asn51Ile、Cys59Arg、Ser108Asn、Ile164Leu）二氢叶酸还原酶有活性的乙胺嘧啶（pyr）衍生物进行了比较分子场分析（CoMFA）。基于三种不同的探针原子C(sp3)（+1）、O(sp3)（-1）和H（+1）对所呈现的CoMFA模型进行了评估，得到了结合三种类型探针原子的最佳模型。统计结果为r(2)(cv)=0.702、S(press)=0.608、r(2)(nv)=0.980、s=0.156以及r(2)(测试集)=0.698，这些结果可以解释约50%的空间贡献。此外，通过使用MP2/6-31G(d,p)量子化学计算，对结合口袋中抑制剂与周围残基之间的特定相互作用能进行了研究。所得结果清楚地表明，Asn108是具有最高排斥相互作用能的pyr抗性的原因。因此，CoMFA和特定相互作用能分析可用于鉴定对四重突变型PfDHFR有活性的强效pyr衍生物的结构特征。
