{"title":"Molecular Modeling and Molecular Dynamics Simulation Studies on the Selective Binding Mechanism of MTHFD2 Inhibitors","authors":"Mengyang Qu","doi":"10.4236/cmb.2022.121001","DOIUrl":null,"url":null,"abstract":"Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial enzyme that plays an important role in purinecarbon metabolism and thymidine biosynthesis. It has attracted broad interest as a novel therapeutic target for cancer. However, a major problem of current MTHFD2 inhibitors is their lack of selectivity and reactivity with its closest isoform, MTHFD1. Recently, the first selective MTHFD2 inhibitor, DS44960156, has been reported and it exhibits a more than 18-fold selectivity for MTHFD2 over MTHFD1. However, mechanism of DS44960156 selective binding to MTHFD2 over MTHFD1 is unknown. In this study, molecular docking, molecular dynamics (MD) simulations, molecular mechanics generalized born/surface area (MM_GBSA) binding free energy calculations, and analysis of the decomposition of binding free energies were used to investigate the selective binding mechanism of DS44960156 to the folate-binding site of MTHFD2 over MTHFD1. The results revealed that contributions from residues Gln100/Gln132, Val55/Asn87, and Gly237/Gly310 in the binding pocket of MTHFD1/MTHFD2 are the key factors responsible for the binding selectivity. These findings explain the selectivity of DS44960156 to MTHFD2 over MTHFD1, and may provide guidance for the future study and design of novel MTHFD2 inhibitors.","PeriodicalId":70839,"journal":{"name":"计算分子生物学(英文)","volume":null,"pages":null},"PeriodicalIF":0.0000,"publicationDate":"2022-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"2","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"计算分子生物学(英文)","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.4236/cmb.2022.121001","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
引用次数: 2
Abstract
Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial enzyme that plays an important role in purinecarbon metabolism and thymidine biosynthesis. It has attracted broad interest as a novel therapeutic target for cancer. However, a major problem of current MTHFD2 inhibitors is their lack of selectivity and reactivity with its closest isoform, MTHFD1. Recently, the first selective MTHFD2 inhibitor, DS44960156, has been reported and it exhibits a more than 18-fold selectivity for MTHFD2 over MTHFD1. However, mechanism of DS44960156 selective binding to MTHFD2 over MTHFD1 is unknown. In this study, molecular docking, molecular dynamics (MD) simulations, molecular mechanics generalized born/surface area (MM_GBSA) binding free energy calculations, and analysis of the decomposition of binding free energies were used to investigate the selective binding mechanism of DS44960156 to the folate-binding site of MTHFD2 over MTHFD1. The results revealed that contributions from residues Gln100/Gln132, Val55/Asn87, and Gly237/Gly310 in the binding pocket of MTHFD1/MTHFD2 are the key factors responsible for the binding selectivity. These findings explain the selectivity of DS44960156 to MTHFD2 over MTHFD1, and may provide guidance for the future study and design of novel MTHFD2 inhibitors.
亚甲基四氢叶酸脱氢酶2 (MTHFD2)是一种线粒体酶,在嘌呤碳代谢和胸腺嘧啶生物合成中起重要作用。它作为一种新的癌症治疗靶点引起了广泛的兴趣。然而,目前MTHFD2抑制剂的一个主要问题是它们缺乏选择性和与其最接近的异构体MTHFD1的反应性。最近,第一个选择性MTHFD2抑制剂DS44960156被报道,它对MTHFD2的选择性比MTHFD1高18倍以上。然而,DS44960156选择性结合MTHFD2而非MTHFD1的机制尚不清楚。本研究采用分子对接、分子动力学(MD)模拟、分子力学广义born/surface area (MM_GBSA)结合自由能计算、结合自由能分解分析等方法,研究DS44960156在MTHFD1上选择性结合MTHFD2叶酸结合位点的机制。结果表明,MTHFD1/MTHFD2结合口袋中的残基Gln100/Gln132、Val55/Asn87和Gly237/Gly310是影响其结合选择性的关键因素。这些发现解释了DS44960156对MTHFD2优于MTHFD1的选择性,可能为未来新型MTHFD2抑制剂的研究和设计提供指导。