PDF(Pubmed)
Abstract：
Isocitrate dehydrogenase 1 (IDH1) is a necessary enzyme for cellular respiration in the tricarboxylic acid cycle. Mutant isocitrate dehydrogenase 1 (mIDH1) has been detected overexpressed in a variety of cancers. mIDH1 inhibitor ivosidenib (AG-120) was only approved by the Food and Drug Administration (FDA) for marketing, nevertheless, a range of resistance has been frequently reported. In this study, several mIDH1 inhibitors with the common backbone pyridin-2-one were explored using the three-dimensional structure-activity relationship (3D-QSAR), scaffold hopping, absorption, distribution, metabolism, excretion (ADME) prediction, and molecular dynamics (MD) simulations. Comparative molecular field analysis (CoMFA, R2 = 0.980, Q2 = 0.765) and comparative molecular similarity index analysis (CoMSIA, R2 = 0.997, Q2 = 0.770) were used to build 3D-QSAR models, which yielded notably decent predictive ability. A series of novel structures was designed through scaffold hopping. The predicted pIC50 values of C3, C6, and C9 were higher in the model of 3D-QSAR. Additionally, MD simulations culminated in the identification of potent mIDH1 inhibitors, exhibiting strong binding interactions, while the analyzed parameters were free energy landscape (FEL), radius of gyration (Rg), solvent accessible surface area (SASA), and polar surface area (PSA). Binding free energy demonstrated that C2 exhibited the highest binding free energy with IDH1, which was -93.25 ± 5.20 kcal/mol. This research offers theoretical guidance for the rational design of novel mIDH1 inhibitors.
摘要：
异柠檬酸脱氢酶1（IDH1）是三羧酸循环中细胞呼吸的必需酶。已检测到突变体异柠檬酸脱氢酶1(mIDH1)在多种癌症中过表达。mIDH1抑制剂ivosidenib（AG-120）仅被美国食品药品监督管理局（FDA）批准上市，然而，一系列的阻力已被频繁报道。在这项研究中,使用三维结构-活性关系（3D-QSAR）探索了几种具有共同骨架吡啶-2-酮的mIDH1抑制剂，脚手架跳跃,吸收，分布，新陈代谢，排泄(ADME)预测，和分子动力学(MD)模拟。比较分子场分析(CoMFA，R2=0.980，Q2=0.765）和比较分子相似性指数分析（CoMSIA，R2=0.997，Q2=0.770)用于构建3D-QSAR模型，这产生了相当不错的预测能力。通过跳台设计了一系列新颖的结构。在3D-QSAR模型中,C3、C6和C9的预测pIC50值较高。此外,MD模拟最终确定了有效的mIDH1抑制剂，表现出强结合相互作用，虽然分析的参数是自由能景观(FEL)，回转半径(Rg),溶剂可及表面积(SASA),和极性表面积（PSA）。结合自由能表明C2与IDH1表现出最高的结合自由能，为-93.25±5.20kcal/mol。本研究为合理设计新型mIDH1抑制剂提供了理论指导。
