Drug Theoretics and Cheminformatics Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata, India.
Med Chem. 2011 May;7(3):173-99. doi: 10.2174/157340611795564295.
Resistance of available antimalarial drugs against Plasmodium species is one of the major problems of malaria control in the developing world. In the present study, we have performed QSAR, pharmacophore mapping and molecular docking studies of cycloguanil derivatives as Plasmodium falciparum dihydrofolate reductase thymidylate synthase (PfDHFR-TS) inhibitors to explore essential features required for the antimalarial activity and important interaction patterns between the enzyme and ligands for the design of new potent PfDHFR-TS inhibitors. The QSAR studies have been carried out using topological parameters along with thermodynamic and structural descriptors. Acceptable values of internal and external validation parameters for the developed QSAR models confirm acceptability of the models. Pharmacophore mapping revealed that two hydrogen bond donor (HBD) features and a hydrophobic feature (HYD) are important parameters for PfDHFR-TS inhibitory activity. The docking studies suggest that the PfDHFR-TS inhibitors interact with Asp54, Ile14, Ile164, ser108, Ser111, Tyr170, Met55, Ala16, Thr185, Leu46, Cys15, Phe58, Ile112, Trp48, Tyr57 and Leu119 amino acid residues. The QSAR, pharmacophore and docking studies inferred that i) branching of the substituents at R1 and R2 positions should be less (small alkyl chain substituents are favored); ii) the electronegativity of the molecules should be high but within some limit; iii) the size and volume of the molecules should be high; iv) molecules should be flexible enough; v) R configuration at C6 position of the triazine ring favors the inhibitory binding affinity; vi) the substituents of the phenyl ring at 3, 4 and 5 position of the phenyl ring should be small hydrophobic groups. Based on these studies, we have designed a library of cycloguanil derivatives with good in silico predicted PfDHFR-TS inhibitory activity.
现有抗疟药物对疟原虫的耐药性是发展中国家疟疾控制的主要问题之一。在本研究中，我们对环胍啶衍生物作为恶性疟原虫二氢叶酸还原酶-胸苷酸合成酶（PfDHFR-TS）抑制剂进行了定量构效关系、药效团映射和分子对接研究，以探索抗疟活性所需的基本特征和酶与配体之间的重要相互作用模式，从而设计新的强效 PfDHFR-TS 抑制剂。QSAR 研究使用拓扑参数以及热力学和结构描述符进行。所开发的 QSAR 模型的内部和外部验证参数的可接受值证实了模型的可接受性。药效团映射表明，两个氢键供体（HBD）特征和一个疏水特征（HYD）是 PfDHFR-TS 抑制活性的重要参数。对接研究表明，PfDHFR-TS 抑制剂与 Asp54、Ile14、Ile164、ser108、Ser111、Tyr170、Met55、Ala16、Thr185、Leu46、Cys15、Phe58、Ile112、Trp48、Tyr57 和 Leu119 氨基酸残基相互作用。QSAR、药效团和对接研究推断：i）R1 和 R2 位置取代基的支化程度应较低（小烷基链取代基有利）；ii）分子的电负性应较高，但在一定范围内；iii）分子的大小和体积应较高；iv）分子应具有足够的柔性；v）三嗪环 C6 位置的 R 构型有利于抑制结合亲和力；vi）苯环 3、4 和 5 位取代基应为小的疏水基团。基于这些研究，我们设计了一个具有良好的 PfDHFR-TS 抑制活性的环胍啶衍生物库。
