Molecular Basis of Bicalutamide Response Alteration of Androgen Receptor Caused by Single Nucleotide Polymorphisms: An In Silico Investigation.

Crit Rev Eukaryot Gene Expr 2019 ;29(2):177-187

Department of Cell and Molecular Biology, Faculty of Science, Semnan University, Semnan, Iran.

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.

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http://dx.doi.org/10.1615/CritRevEukaryotGeneExpr.2019026432DOI Listing
February 2020

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