ERp57 Protein Activators for Management of Fertility by Virtual Screening and Molecular Dynamic Studies

Abstract

Objective(s): Infertility is a highly complex disorder of the genitalia with important medical and psychological issues. –Despite many efforts to treat infertility, pregnancy outcomes are meager (<12%). Defective sperm-Zona Pellucida (ZP) binding and penetration are the leading causes of zero fertilization rates. ERp57, a protein disulfide isomerase, is on the surfaces of spermatozoa, which enables sperm to penetrate the ZP. Up-regulation of the surface thiol content regulates human spermatozoa-ZP binding. ERp57 is a part of a spermatozoa-ZP receptor complex and a protein disulfide isomerase that regulates the thiol-disulfide exchange reactions of proteins. The binding site of calcitriol on the surfaces of ERp57 plays an indirect role in male fertility. Docking was used to finding calcitriol's possible binding mode on ERp57 and generate the structure-based pharmacophore model. Then the developed model was used to screen the Maybridge library to find non-steroidal analogs of calcitriol. Subsequently, forty-eight compounds were matched to the pharmacophore model and retrieved from the Maybridge library. All retrieved compounds were docked on the ERp57 binding pocket to analyze the molecular interactions and binding energy. The top twenty compounds with the highest binding energy were chosen for further analysis. Three compounds were selected for further evaluation by molecular dynamic simulation for 50 nanoseconds. Finally, compound 20, (2-[1-[4-(2-Methylpropyl)phenyl]ethyl]-5-(3-nitrophenyl)-1,3,4-oxadiazole) with higher similarity to calcitriol provides proper complex stability during the time of simulations, binding affinity, and binding energy even better than the calcitriol, in the active site of ERp57. Compound 20 with 1,3,4-oxadiazole core was introduced as a novel and potential ERp57 agonist to treat ERp57-related infertility.