Hydrocortisone Probutate

Psoriasis is a chronic inflammatory disease causing itching in the body and pain in the joints. Currently, no permanent cure is available at a commercial level for this disease. Genome wide association studies (GWAS) provide a deeper insight that helps in better understanding this disease and further possible cure of this disease. The major goal of the present study is to identify potent genetic targets of psoriasis disease using GWAS approach and identify drugs for repurposing. The methods used include GWAS catalogue, GeneAnalytics, canSAR protein annotation tool, VarElect, Drug bank, Proteomics database, ProTox software. By exploring GWAS catalogue, 126 psoriasis associated genes (PAG) were identified. 68 genes found to be druggable were obtained from canSAR protein annotation tool. Localization results depict that maximum genes are present in cytoplasmic cellular components. The superpathways obtained from GeneAnalytics resulted in involvement of these genes in the immune system, Jak/Stat pathway, Th17 and Wnt pathways. Two genes Interleukin 13 (IL13) and POLI are Food and Drug Administration (FDA) approved targets. Small compounds for these targets were analysed for drug-likeliness, toxicity and mutagenecity properties. The FDA approved drug pandel was found to possess desirable properties. The medications used for psoriasis causes mild to severe side effects and does not work well always. Hence we propose drug repurposing strategy to use existing drugs for new therapies. Therefore, the drug pandel could be explored further and repurposed to treat psoriasis.

The androgen receptor (AR) plays important roles in gene expression regulation, sexual phenotype maintenance, and prostate cancer (PCa) development. The communications between the AR ligand-binding domain (LBD) and its coactivator are critical to the activation of AR. It is still unclear how the ligand binding would affect the AR-coactivator interactions. In this work, the effects of the ligand binding on the AR-coactivator communications were explored by molecular dynamics (MD) simulations. The results showed that the ligand binding regulates the residue interactions in the function site AF-2. The ligand-to-coactivator allosteric pathway, which involves the coactivator, helix 3 (H3), helix 4 (H4), the loop between H3 and H4 (L3), and helix 12 (H12), and ligands, was characterized. In addition, the interactions of residues on the function site BF-3, especially on the boundary of AF-2 and BF-3, are also affected by the ligands. The MM/GBSA free energy calculations demonstrated that the binding affinity between the coactivator and apo-AR is roughly weaker than those between the coactivator and antagonistic ARs but stronger than those between the coactivator and agonistic ARs. The results indicated that the long-range electrostatic interactions and the conformational entropies are the main factors affecting the binding free energies. In addition, the F876L mutation on AR-LBD affects the ligand-to-coactivator allosteric pathway, which could be the reason for point mutation induced tolerance for the antagonistic drugs such as enzalutamide. Our study would help to develop novel drug candidates against PCa.