7 research outputs found
Table_1_Structural Changes Due to Antagonist Binding in Ligand Binding Pocket of Androgen Receptor Elucidated Through Molecular Dynamics Simulations.DOCX
<p>When a small molecule binds to the androgen receptor (AR), a conformational change can occur which impacts subsequent binding of co-regulator proteins and DNA. In order to accurately study this mechanism, the scientific community needs a crystal structure of the Wild type AR (WT-AR) ligand binding domain, bound with antagonist. To address this open need, we leveraged molecular docking and molecular dynamics (MD) simulations to construct a structure of the WT-AR ligand binding domain bound with antagonist bicalutamide. The structure of mutant AR (Mut-AR) bound with this same antagonist informed this study. After molecular docking analysis pinpointed the suitable binding orientation of a ligand in AR, the model was further optimized through 1 μs of MD simulations. Using this approach, three molecular systems were studied: (1) WT-AR bound with agonist R1881, (2) WT-AR bound with antagonist bicalutamide, and (3) Mut-AR bound with bicalutamide. Our structures were very similar to the experimentally determined structures of both WT-AR with R1881 and Mut-AR with bicalutamide, demonstrating the trustworthiness of this approach. In our model, when WT-AR is bound with bicalutamide, Val716/Lys720/Gln733, or Met734/Gln738/Glu897 move and thus disturb the positive and negative charge clumps of the AF2 site. This disruption of the AF2 site is key for understanding the impact of antagonist binding on subsequent co-regulator binding. In conclusion, the antagonist induced structural changes in WT-AR detailed in this study will enable further AR research and will facilitate AR targeting drug discovery.</p
Additional file 1: of A pharmacogenetic signature of high response to Copaxone in late-phase clinical-trial cohorts of multiple sclerosis
A comprehensive summary of sample sizes and cohorts in pharmacogenetics studies in the field of multiple sclerosis. (DOCX 23 kb
Additional file 12: of A pharmacogenetic signature of high response to Copaxone in late-phase clinical-trial cohorts of multiple sclerosis
Details on participating institutional or clinical sites at which Institutional Review Boards or Ethics Committees approved the clinical trials included in the study. (DOCX 59 kb
Additional file 5: of Large-scale transcriptomic analysis reveals that pridopidine reverses aberrant gene expression and activates neuroprotective pathways in the YAC128 HD mouse
Table S5. Pathway analysis of alternatively spliced genes identified after high dose treatment with pridopidine. (XLSX 31 kb
Additional file 3: of Large-scale transcriptomic analysis reveals that pridopidine reverses aberrant gene expression and activates neuroprotective pathways in the YAC128 HD mouse
Table S3. Transcription factor enrichment analysis of genes differentially expressed in the mouse striatum. (XLSX 18 kb
Additional file 1: of Large-scale transcriptomic analysis reveals that pridopidine reverses aberrant gene expression and activates neuroprotective pathways in the YAC128 HD mouse
Table S1. Adjusted p-val range and fold change range for differential expression and DUEJ genes meeting adj p-val < 0.05 cutoff. (XLSX 11 kb
Additional file 4: of Large-scale transcriptomic analysis reveals that pridopidine reverses aberrant gene expression and activates neuroprotective pathways in the YAC128 HD mouse
Table S4. qPCR validation of striatal gene expression identified in RNAseq and pathway analysis. (XLSX 10 kb