Identification of receptor-interacting protein kinase 3 inhibitor for atherosclerosis

Cardiovascular diseases are the major cause of death worldwide. Atherosclerosis is a chronic inflammatory condition characterized by the accumulation of atherosclerotic plaques in the artery walls of medium and large arteries. Receptor-interacting protein kinase 3 (RIPK3) plays a major role in the development and instability of atherosclerotic plaque. Targeting RIPK3 is a promising therapeutic approach, as current inhibitors have reported side effects and lack specificity. In order to identify new and targeted RIPK3 inhibitors, this study focused on computational approach using methods such as virtual screening with essential descriptors such as drug-likeness and pharmacokinetic properties and docking studies. Three top compounds viz. ZINC96307758, ZINC96136342 and ZINC40012267 were identified that exhibit better binding scores compared to the reference inhibitor GSK843. Further analysis using density functional theory showed that the top compound was more reactive and stable compared to GSK843. The two complexes RIPK3-ZINC40012267 and RIPK3-ZINC96307758 showed the best stability, based on molecular dynamics simulations, as shown by its favorable free energy landscape and low RMSD and RMSF values. Strong binding free energy for the top hits was validated by MMPBSA calculations. Our results point to ZINC40012267 and ZINC96307758 as a particularly strong and stable RIPK3 inhibitor candidate, wet bench experimental validations are required to establish this finding.