Strategies for in Silico Drug Discovery to Modulate Macromolecular Interactions Altered by Mutations.

IF 3.3 Q2 BIOCHEMISTRY & MOLECULAR BIOLOGY
Pitambar Poudel, Maria A Miteva, Emil Alexov
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引用次数: 0

Abstract

Most human diseases have genetic components, frequently single nucleotide variants (SNVs), which alter the wild type characteristics of macromolecules and their interactions. A straightforward approach for correcting such SNVs-related alterations is to seek small molecules, potential drugs, that can eliminate disease-causing effects. Certain disorders are caused by altered protein-protein interactions, for example, Snyder-Robinson syndrome, the therapy for which focuses on the development of small molecules that restore the wild type homodimerization of spermine synthase. Other disorders originate from altered protein-nucleic acid interactions, as in the case of cancer; in these cases, the elimination of disease-causing effects requires small molecules that eliminate the effect of mutation and restore wild type p53-DNA affinity. Overall, especially for complex diseases, pathogenic mutations frequently alter macromolecular interactions. This effect can be direct, i.e., the alteration of wild type affinity and specificity, or indirect via alterations in the concentration of the binding partners. Here, we outline progress made in methods and strategies to computationally identify small molecules capable of altering macromolecular interactions in a desired manner, reducing or increasing the binding affinity, and eliminating the disease-causing effect. When applicable, we provide examples of the outlined general strategy. Successful cases are presented at the end of the work.

调控突变改变的大分子相互作用的计算机药物发现策略。
大多数人类疾病都有遗传成分,通常是单核苷酸变异(SNVs),它改变了大分子的野生型特征及其相互作用。纠正这种与snv相关的改变的一种直接方法是寻找可以消除致病作用的小分子、潜在药物。某些疾病是由蛋白质-蛋白质相互作用的改变引起的,例如,Snyder-Robinson综合征,其治疗重点是发展小分子,恢复精胺合酶的野生型同二聚化。其他疾病源于蛋白质-核酸相互作用的改变,如癌症;在这些情况下,消除致病效应需要小分子来消除突变的影响并恢复野生型p53-DNA亲和力。总的来说,特别是对于复杂的疾病,致病突变经常改变大分子的相互作用。这种影响可以是直接的,即野生型亲和力和特异性的改变,也可以是间接的,通过改变结合伴侣的浓度。在这里,我们概述了在计算识别能够以期望的方式改变大分子相互作用、减少或增加结合亲和力和消除致病作用的小分子的方法和策略方面取得的进展。在适用的情况下,我们将提供概述总体策略的示例。在工作的最后介绍了成功的案例。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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CiteScore
3.50
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0.00%
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