Ojha Probir Kumar, Roy Kunal
Drug Theoretics and Cheminformatics Laboratory, Division of Medicinal and Pharmaceutical Chemistry, Department of Pharmaceutical Technology, Jadavpur University, Kolkata 700 032, India.
Comb Chem High Throughput Screen. 2013 Nov;16(9):739-57. doi: 10.2174/13862073113169990002.
Multi-drug resistance to the available antimalarial drugs is a major threat for malaria treatment. Due to the recent characterization of human and parasite genome sequences, both ligand and target based drug design strategies may be helpful for the design of potential antimalarial compounds with reduced degree of resistance. The present work deals with quantitative structure-activity relationship (QSAR) modeling, pharmacophore mapping and docking studies of a series of 95 nucleoside analogs as inhibitors of Plasmodium falciparum deoxyuridine-5'-triphosphate nucleotidohydrolase (PfdUTPase), an enzyme involved in nucleotide metabolism that acts as a first line of defence against uracil incorporation into DNA. The QSAR and pharmacophore models were validated both internally and externally showing good statistical results. The docking study was performed and validated using three different software tools namely Discovery Studio 2.1 (Accelrys), Maestro 9.3 (Schrodinger) and MOE (Chemical Computing Group). The QSAR studies revealed that compounds containing substituted aromatic carbons (aasC fragment) and those bearing hydroxyl groups without an noxolane ring exert potent PfdUTPase inhibitory activity. The best pharmacophore hypothesis (hypothesis 1) possessed four features: (i) one hydrogen bond donor (HBD), (ii) one hydrogen bond acceptor (HBA), (iii) one hydrophobic (HYD) and (iv) one ring aromatic (RA). The docking studies revealed that the PfdUTPase inhibitors interact with a pocket containing Phe46, Lys48, Leu88, Asn103, Gly106, Leu107, Ile108, Tyr112, Ile116, Ile117, Ala118 and Ala119 amino acid residues. The interaction pattern of all the PfdUTPase inhibitors was almost same in case of docking using Discovery Studio 2.1, Maestro 9.3 and MOE software. This work thus presents the first QSAR report for nucleoside analogs which may serve as an efficient tool to address the increasing threat of malaria in the developing countries.
对现有抗疟药物的多药耐药性是疟疾治疗的一大威胁。由于近期对人类和寄生虫基因组序列的表征，基于配体和靶点的药物设计策略可能有助于设计出耐药性较低的潜在抗疟化合物。目前的工作涉及对一系列95种核苷类似物进行定量构效关系（QSAR）建模、药效团映射和对接研究，这些核苷类似物作为恶性疟原虫脱氧尿苷-5'-三磷酸核苷酸水解酶（PfdUTPase）的抑制剂，该酶参与核苷酸代谢，是防止尿嘧啶掺入DNA的第一道防线。QSAR和药效团模型在内部和外部均得到验证，显示出良好的统计结果。使用三种不同的软件工具进行了对接研究并验证，这三种工具分别是Discovery Studio 2.1（Accelrys公司）、Maestro 9.3（薛定谔公司）和MOE（化学计算集团）。QSAR研究表明，含有取代芳香碳（aasC片段）的化合物以及那些带有羟基且没有诺索兰环的化合物具有强大的PfdUTPase抑制活性。最佳药效团假设（假设1）具有四个特征：（i）一个氢键供体（HBD），（ii）一个氢键受体（HBA），（iii）一个疏水基团（HYD）和（iv）一个环状芳香基团（RA）。对接研究表明，PfdUTPase抑制剂与一个包含苯丙氨酸46、赖氨酸48、亮氨酸88、天冬酰胺103、甘氨酸106、亮氨酸107、异亮氨酸108、酪氨酸112、异亮氨酸116、异亮氨酸117、丙氨酸118和丙氨酸119氨基酸残基的口袋相互作用。在使用Discovery Studio 2.1、Maestro 9.3和MOE软件进行对接时，所有PfdUTPase抑制剂的相互作用模式几乎相同。因此，这项工作提出了首个关于核苷类似物的QSAR报告，这可能成为应对发展中国家日益严重的疟疾威胁的有效工具。
Zotero 插件