Department of Chemistry, K.N.Toosi University of Technology, Tehran, Iran.
Super Computing Institute, University of Tehran, Tehran, Iran.
J Biomol Struct Dyn. 2023 May;41(8):3667-3679. doi: 10.1080/07391102.2022.2053745. Epub 2022 Mar 23.
Dihydrofolate reductase (DHFR) is a ubiquitous cellular enzyme involved in the biosynthesis of nucleotide and protein precursors, thus, the inhibition of human DHFR can be a promising strategy in cancer treatment. The design of effective anticancer drugs is an urgent need today according to the high spread of cancer. The indole molecule with diverse mechanisms of action and anticancer properties is one of the efficient pharmacophores in drug design. Hence, a virtual library of indole derivatives as a scaffold was selected for designing safer and more effective anticancer drugs against DHFR in this work. All indole derivatives utilized in the library design were selected regarding appreciable tumor growth inhibition. Structure-activity relationship (SAR), docking energy, ADMET (absorption, distribution, metabolism, excretion, and toxicity) parameters, and effective non-covalent interactions were used to identify potential anticancer with indole scaffold. Results showed a higher number of indole moieties provide a strong attachment to the DHFR binding pocket and therefore more effective anticancer activity. The indole scaffold in combination with dichlorobenzene improves DHFR inhibition whereas barbituric acid weakens inhibition activity. In the following to validate the docking results, Molecular dynamics (MD) simulation and molecular mechanics generalized-Born surface area (MM-GBSA) indicated the permanent stability of the selected ligands into the DHFR binding pocket and the key amino acids. Therefore, promising pharmacophores based on indole-DHFR interactions were discovered, and the outcome could be useful in guiding future and drug discovery in cancer medicine.Communicated by Ramaswamy H. Sarma.
二氢叶酸还原酶（DHFR）是一种普遍存在的细胞酶，参与核苷酸和蛋白质前体的生物合成，因此，抑制人 DHFR 可能是癌症治疗的一种有前途的策略。根据癌症的高传播率，今天迫切需要设计有效的抗癌药物。具有多种作用机制和抗癌特性的吲哚分子是药物设计中有效的药效团之一。因此，在这项工作中，选择了一个作为支架的吲哚衍生物虚拟库，用于设计针对 DHFR 的更安全、更有效的抗癌药物。库设计中使用的所有吲哚衍生物均选择具有相当的肿瘤生长抑制作用。结构-活性关系（SAR）、对接能、ADMET（吸收、分布、代谢、排泄和毒性）参数以及有效的非共价相互作用用于鉴定具有吲哚支架的潜在抗癌药物。结果表明，更多的吲哚部分提供了与 DHFR 结合口袋更强的附着，因此具有更强的抗癌活性。吲哚支架与二氯苯结合可增强 DHFR 抑制作用，而巴比妥酸则减弱抑制活性。为了验证对接结果，随后进行了分子动力学（MD）模拟和分子力学广义 Born 表面积（MM-GBSA），结果表明所选配体永久稳定地结合到 DHFR 结合口袋和关键氨基酸上。因此，发现了基于吲哚-DHFR 相互作用的有前途的药效团，这一结果可能有助于指导癌症医学中的未来药物发现。由 Ramaswamy H. Sarma 交流。
