Identification of a Novel Antagonist of the PDIA1 Reductase Activity Using Virtual Screening PDF

Keywords

Protein Disulfide Isomerase, Thrombosis, Virtual Screening, Molecular docking, Inflammation.

Abstract

Protein Disulfide Isomerase (PDI) protein family is known for assisting newly synthesized proteins to fold in the endoplasmic reticulum (ER) of most cell types. Meanwhile, extracellular functions of PDIs have been reported and associated to several processes including cell adhesion, thrombosis, cancer, and pathogenesis. In addition to their biological significance, the expression profile, localization and suitability for high-throughput screening are in favor of PDIs being good targets in the development of drug against several diseases. Indeed, few PDI inhibitors are available and show decreased specificity, potency and druggability. In an attempt to identify more potent and specific PDIA1 inhibitors, we have carried out virtual screening of a large chemical compound database (107 compounds). Following this screening, we used an experimental plate-based PDIA1 reductase activity inhibition assay screening to identify and validate a lead compound for further optimization using combinatorial synthesis and computational drug design. Indeed, we identified a molecule that could be used as a lead candidate for the development of anti-inflammatory drugs.