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Molecular Basis of Bicalutamide Response Alteration of Androgen Receptor Caused by Single Nucleotide Polymorphisms: An In Silico Investigation.
Critical Reviews in Eukaryotic Gene Expression ( IF 1.6 ) Pub Date : 2019-01-01 , DOI: 10.1615/critreveukaryotgeneexpr.2019026432
Noushin Hadian 1 , Farzaneh Mohamadi Farsani 2 , Mohamad Reza Ganjalikhany 2 , Hossein Sazegar 1 , Mehdi Sadeghi 3
Affiliation  

The vast majority of drugs act through binding to their protein targets. Prediction of the interaction between small molecules and these receptors is a key element in the process of drug discovery. Advances in structural biology have enabled us to resolve the three-dimensional structure of proteins, which are the targets of the drugs. Pharmacogenetics also helped researchers to study the structural variations arise from the single nucleotide polymorphisms (SNPs) and to survey the effects these variations in drug design and development. These improvements led to the identification of structural changes caused by SNPs, which affect the drug interaction with their receptors, called drug response. In this study, the interaction between androgen receptor and bicalutamide was investigated using a computational analysis. The results of these analyses were then used for identification of nonsynonymous SNPs that are potentially involved in drug response alterations. The data show that amino acids Met895, Trp741, Arg752, Ile899, Leu707, Gly708, Gln711, Met745, Met749, Thr877, Phe764, Met742, Asn705 and Leu704 are the main residues involved in the interaction between androgen receptor and bicalutamide. The occurrence of nonsynonymous polymorphisms I843T, L708R, H690P, I870M, N757S, L713F, G744E, L678P, M788V, M781I, A722T, H875Y, I842V, and F827L in this receptor greatly affected its interaction with bicalutamide, and they were able to cause drug resistance. The results of this study could be useful in predicting the response to treatment in patients receiving bicalutamide.

中文翻译:

单核苷酸多态性引起的比卡鲁胺应答性雄激素受体改变的分子基础:计算机研究。

绝大多数药物通过与蛋白质靶标结合而起作用。小分子与这些受体之间相互作用的预测是药物发现过程中的关键要素。结构生物学的进步使我们能够解决蛋白质的三维结构,蛋白质是药物的靶标。药物遗传学还帮助研究人员研究由单核苷酸多态性(SNP)引起的结构变异,并调查这些变异对药物设计和开发的影响。这些改进导致鉴定了由SNP引起的结构变化,这些结构变化影响药物与其受体的相互作用,称为药物反应。在这项研究中,雄激素受体和比卡鲁胺之间的相互作用进行了计算分析。然后将这些分析的结果用于识别可能与药物反应改变有关的非同义SNP。数据显示,氨基酸Met895,Trp741,Arg752,Ile899,Leu707,Gly708,Gln711,Met745,Met749,Thr877,Phe764,Met742,Asn705和Leu704是参与雄激素受体与比卡鲁胺之间相互作用的主要残基。该受体中非同义多态性I843T,L708R,H690P,I870M,N757S,L713F,G744E,L678P,M788V,M781I,A722T,H875Y,I842V和F827L的出现极大地影响了其与比卡鲁胺的相互作用,并且能够引起药物滥用抵抗性。这项研究的结果可能有助于预测接受比卡鲁胺治疗的患者的治疗反应。
更新日期:2019-11-01
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