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首页> 外文期刊>Journal of Biomolecular Structure and Dynamics >Identification of potential inhibitors against pathogenic missense mutations of PMM2 using a structure-based virtual screening approach
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Identification of potential inhibitors against pathogenic missense mutations of PMM2 using a structure-based virtual screening approach

机译：使用基于结构的虚拟筛选方法鉴定PMM2致病致畸变突变的潜在抑制剂

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The autosomal recessive phosphomannomutase 2-congenital disorder of glycosylation (PMM2-CDG) is characterized by defective functioning of the PMM2 enzyme, which is necessary for the conversion of mannose-6-phosphate into mannose-1-phosphate. Here, a computational pipeline was drawn to identify the most significant mutations, and further, we used a virtual screening approach to identify a new lead compound to treat the identified significant mutations. We searched for missense mutation data related to PMM2-CDG in HGMD (R), UniProt, and ClinVar. Our search yielded a total of 103 mutations, of which 91 are missense mutations. The D65Y, I132N, I132T, and F183S mutations were classified as deleterious, destabilizing, and altering the biophysical properties using the PredictSNP, iStable, and Align GVGD in silico prediction tools. Additionally, we applied a multistep protocol to screen for an alternative lead compound to the existing CID2876053 (1-(3-chlorophenyl)-3,3-bis(pyridine-2-yl)urea) with affinity to these identified significant mutants. Two compounds, CHEMBL1491007 (6-chloro-4-phenyl-3-(4-pyridin-2-ylpiperazin-1-yl)-1H-quinolin-2-one) and CHEMBL3653029 (5-chloro-4-[6-[(3-fluorophenyl)methylamino]pyridin-2-yl]-N-(piperidin-4-ylmethyl)pyridin-2-amine), exhibited the highest binding affinity with the selected mutants and were chosen for further analysis. Through molecular docking, molecular dynamics simulation, and MMPBSA analysis, we found that the known compound, i.e. CID2876053, has stronger interaction with the D65Y mutant. The newly identified lead compound CHEMBL1491007 showed stronger interaction with the I132N and I132T mutants, whereas the most deleterious mutant, F183S, showed stronger interaction with CHEMBL3653029. This study is expected to aid in the field of precision medicine, and further to in vivo and in vitro analysis of these lead compounds might shed light on the treatment of PMM2-CDG. Communicated by Ramaswamy H. Sarma
机译：常染色体隐性遗传磷酸甘露突变酶2-先天性糖基化障碍（PMM2-CDG）的特征是PMM2酶功能缺陷，这是甘露糖-6-磷酸转化为甘露糖-1-磷酸所必需的。在这里，我们绘制了一条计算管道来识别最显著的突变，并且进一步，我们使用虚拟筛选方法来识别一种新的先导化合物来治疗已识别的显著突变。我们在HGMD（R）、UniProt和ClinVar中搜索与PMM2-CDG相关的错义突变数据。我们的研究总共产生了103个突变，其中91个是错义突变。D65Y、I132N、I132T和F183S突变被分类为有害的、不稳定的，并使用PredictSNP、iStable和Align GVGD在硅片预测工具中改变生物物理性质。此外，我们采用了一个多步骤方案来筛选现有CID2876053（1-（3-氯苯基）-3,3-双（吡啶-2-基）脲）的替代先导化合物，该化合物与这些已鉴定的重要突变体具有亲和力。两种化合物CHEMBL1491007（6-氯-4-苯基-3-（4-吡啶-2-基哌嗪-1-基）-1H-喹啉-2-酮）和CHEMBL3653029（5-氯-4-[6-[（3-氟苯基）甲氨基]吡啶-2-基]-N-（哌啶-4-基甲基）吡啶-2-胺）与所选突变体表现出最高的结合亲和力，并被选择用于进一步分析。通过分子对接、分子动力学模拟和MMPBSA分析，我们发现已知化合物CID2876053与D65Y突变体具有更强的相互作用。新发现的先导化合物CHEMBL1491007与I132N和I132T突变体表现出更强的相互作用，而最有害的突变体F183S与CHEMBL3653029表现出更强的相互作用。这项研究有望在精密医学领域提供帮助，进一步对这些先导化合物进行体内和体外分析可能有助于PMM2-CDG的治疗。由Ramaswamy H.Sarma传达

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