Molecular Bio-computation and Drug Design Laboratory, School of Health Sciences, University of KwaZulu-Natal, Westville Campus, Durban 4001, South Africa.
Department of Chemistry, Faculty of Science, University of Tabuk, Tabuk, 7149, Saudi Arabia.
Anticancer Agents Med Chem. 2023;23(8):953-966. doi: 10.2174/1871520623666221129163001.
Heterozygous mutations in the cytoplasmic and mitochondrial isoforms of isocitrate dehydrogenase enzymes 1 and 2 subtypes have been extensively exploited as viable druggable targets, as they decrease the affinity of isocitrate and higher affinity of D-2-hydroxyglutarate, an oncometabolite.
Vorasidenib (AG-881) has recently been reported as a promising dual inhibitor of mutant isocitrate dehydrogenase 1 and 2 with the ability to penetrate the blood-brain barrier towards the treatment of low-grade glioma. In order to combat drug resistance and toxicity levels, this compelled us to further investigate this substance as a basis for the creation of potential selective inhibitors of mutant isocitrate dehydrogenases 1 and 2.
By employing a wide range of computational techniques, binding moieties of AG-881 that contributed towards its selective binding to isocitrate dehydrogenase enzymes 1 and 2 were identified and subsequently used to generate pharmacophore models for the screening of potential inhibitor drugs that were further assessed by their pharmacokinetics and physicochemical properties.
AG-881 was identified as the most favorable candidate for isocitrate dehydrogenase enzyme 1, exhibiting a binding free energy of -28.69 kcal/mol. ZINC93978407 was the most favorable candidatefor isocitrate dehydrogenase enzyme 2, displaying a strong binding free energy of -27.10 kcal/mol. ZINC9449923 and ZINC93978407 towards isocitrate dehydrogenase enzyme 1 and 2 showed good protein structural stability with a low radius of gyration values relative to AG-881.
We investigated that ZINC9449923 of isocitrate dehydrogenase enzyme 1 and ZINC 93978407 of isocitrate dehydrogenase enzyme 2 could serve as promising candidates for the treatment of lower-grade glioma as they cross the blood-brain barrier, and present with lower toxicity levels relative to AG-881.
异柠檬酸脱氢酶 1 和 2 亚型的细胞质和线粒体同工酶的杂合突变已被广泛用作可行的药物靶点，因为它们降低了异柠檬酸的亲和力和更高亲和力的 D-2-羟戊二酸，一种致癌代谢物。
Vorasidenib（AG-881）最近被报道为一种有前途的突变型异柠檬酸脱氢酶 1 和 2 的双重抑制剂，具有穿透血脑屏障治疗低级别神经胶质瘤的能力。为了对抗药物耐药性和毒性水平，这促使我们进一步研究这种物质，作为创建潜在的突变型异柠檬酸脱氢酶 1 和 2 选择性抑制剂的基础。
通过采用广泛的计算技术，确定了 AG-881 的结合部分，这些部分有助于其对异柠檬酸脱氢酶 1 和 2 的选择性结合，并随后用于生成用于筛选潜在抑制剂药物的药效团模型，这些药物进一步通过其药代动力学和物理化学性质进行评估。
AG-881 被确定为异柠檬酸脱氢酶 1 的最有利候选物，表现出-28.69 kcal/mol 的结合自由能。ZINC93978407 是异柠檬酸脱氢酶 2 的最有利候选物，表现出-27.10 kcal/mol 的强结合自由能。ZINC9449923 和 ZINC93978407 对异柠檬酸脱氢酶 1 和 2 显示出良好的蛋白质结构稳定性，与 AG-881 相比，回转半径值较低。
我们研究了 ZINC9449923 异柠檬酸脱氢酶 1 和 ZINC 93978407 异柠檬酸脱氢酶 2 可以作为治疗低级别神经胶质瘤的有前途的候选物，因为它们可以穿过血脑屏障，并且与 AG-881 相比，毒性水平较低。
