Conceptual design of hybrid PCSK9 lead inhibitors against coronary artery disease

Abstract

Abstract The enzyme, Proprotein Convertase Subtilisin Kexin type-9 (PCSK 9) inhibition serves as a significant target to prevent the risk of Coronary Artery Disease. Hence, this work is focused on the exploration of novel PCSK 9 lead inhibitors through In silico approach. In abidance to the study, BREED algorithm has been taken to design novel hybridised ligands. Subsequently, various in silico screening studies were performed in Biovia Discovery Studio 2017. Novel ligand generation protocol generated 595 hybridised ligands from the 51 parent scaffolds. These ligands were mapped and screened by ludi interactions of the active site PCSK 9 and were reduced to 245 hit compounds. The docking studies showed that the berberine skeleton contained molecule possessed CDOCKER energy (−13.5582 Kcal/mol) and formed strong interactions with Arg93, Arg97 and His137 residues. The developed pharmacophore model revealed that hydrogen bond acceptor and negative ionizable charges are necessary for the inhibition of PCSK 9. The mapping of pharmacophore model confirmed that 96 molecules were as best fit. Finally, toxicity and dynamic simulation studies confirmed that safe and stable complex formation between lead molecules and PCSK 9 receptor. The results concluded that the 15 lead molecules are proved as potent and safe PCSK9 inhibitors.