Identification of novel small molecule inhibitors for endoplasmic reticulum oxidoreductase 1α (ERO1α) enzyme: structure-based molecular docking and molecular dynamic simulation studies.

The endoplasmic reticulum (ER) is a cellular organelle responsible for the folding of proteins. When protein folding demand exceeds the folding capacity, cells trigger ER stress. ER-oxidoreductase 1α (ERO1α) is an ER stress component that controls oxidative folding protein. Upregulation of ERO1α was reported in distinct types of cancer including breast cancer and colon cancer. It was reported that deletion of ERO1 gene compromised cancer progression and cell proliferation in colon cancer. Thereby, ERO1α inhibition might be a clinically promising anti-cancer therapeutic target. In the present study, we conducted a virtual screening of 6,000 natural-product molecules obtained from Zinc database using a multistep docking approach with a crystal structure of human ERO1α. Our analyses from high throughput virtual screening revealed the top-ranked scores of 3000 molecules with glide scores of less than -4.0 kcal/mol. These molecules were further advanced to standard precision (SP) docking. The top 300 molecules of SP docking with glide scores ≤ -7.5 kcal/mol were chosen to undergo extra precision (XP) docking. Around 40 molecules that have conserved interactions with the binding site of ERO1α were ranked by the XP docking. Based on visual inspection, seven-candidate molecules that have high binding affinity scores and more molecular interactions were shortlisted. The dynamic stability of binding between the candidate molecules and ERO1α was characterized using 100 nanoseconds molecular dynamics simulation method. Two candidates exhibited strong and stable binding complexes with ERO1α. Collectively, these findings suggest that the identified molecules may serve as potential anti-cancer lead molecules subjected to further experimental validation. Communicated by Ramaswamy H. Sarma.