Cheminformatics Modeling of Adverse Drug Responses by Clinically Relevant Mutants of Human Androgen Receptor

The human androgen receptor (AR) is a ligand-activated transcription factor that plays a pivotal role in the development and progression of prostate cancer (PCa). Many forms of castration-resistant prostate cancer (CRPC) still rely on the AR for survival. Currently used antiandrogens face clinical limitations as drug resistance develops in patients over time since they all target the mutation-prone androgen binding site (ABS), where gain-of-function mutations eventually convert antagonists into agonists. With a significant number of reported distinct mutations located across the ABS, it is imperative to develop a prognostic platform which would equip clinicians with prior knowledge and actionable strategies if cases of previously unreported AR mutations are encountered. The goal of this study is to develop a theoretical approach that can predict such previously unreported AR mutants in response to current treatment options for PCa. The expected drug response by these mutants has been modeled using cheminformatics methodology. The corresponding QSAR pipeline has been created, which extracts key protein–ligand interactions and quantifies them by 4D molecular descriptors. The developed models reported with an accuracy reaching 90% and enable prediction of activation of AR mutants by its native ligand as well as assess whether known antiandrogens will act on them as agonists or antagonists. As a result, a previously uncharacterized mutant, T878G, has been predicted to be activated by the latest antiandrogen enzalutamide, and the corresponding experimental evaluation confirmed this prediction. Overall, the developed cheminformatics pipeline provides useful insights toward understanding the changing genomic landscape of advanced PCa

Additional file 3: Figure S2. of Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients

Activation of wild-type AR by dihydrotestosterone (DHT), progesterone, estradiol, and hydrocortisone. The graphs represent the average ± SEM of three independent experiments with four replicates each. (TIF 252 kb

Additional file 1: Table S1. of Functional analysis of androgen receptor mutations that confer anti-androgen resistance identified in circulating cell-free DNA from prostate cancer patients

The results of the validation of a subset of detected mutations on MiSeq, Illumina. The run was designed to test 23 mutations in 11 cfDNA samples (both amplified and non-amplified). WGA samples are marked with *, n/a – sample not sequenced on MiSeq. Only two calls were not supported on MiSeq. S889G call in VC-012-t1 unamplified cfDNA was not detected on original 454 run, or on MiSeq resequencing. (DOCX 23 kb