Pharmacoinformatics Approaches to Probe Current Paradigm Shift in Hypercholesterolemia

Abstract

Statins (hydroxymethyl-glutaryl coenzyme A reductase inhibitors) is well known for its activity to reduce “bad” low density lipoprotein (LDL) cholesterol concentrations and cardiovascular risk. Therefore, Statins therapy along with better diet and more exercise, almost halves the rate of coronary event when compared with an “unfavourable lifestyle.” However, it has been demonstrated by various authors that statins cause unacceptable adverse effects and is inadequate to control LDL cholesterol even when combined with lifestyle changes. Briefly, LDL receptors on the surface of hepatocytes bind circulating LDL cholesterol and are then endocytosed. Within the cell, receptors are either recycled or degraded. Recently it has been identified that, people with familial hypercholesterolemia have particularly high concentrations of LDL cholesterol due to gain in function mutation in PCSK9 (proprotein convertase-subtilisin/kexin type 9) gene that causes abnormal degradation of LDL receptors (LDLR) which may hamper the LDL degradation that ultimately leads to elevate the concentration of LDL in plasma. Previous studies demonstrate that people with very low LDL cholesterol concentrations have gene mutations that cause loss of function of the enzyme PCSK9. Therefore, if PCSK9 is inhibited more LDL receptors are recycled to the cell surface, where they can take up more LDL cholesterol. Towards this goal, in present project structure guided virtual screening protocol has been designed to elucidate the PCSK9 liability of new chemical entities. In the current project, molecular docking studies highlighted that amino acid residues ARG194, ARG237, ASP367, ASP374-SER381 are involved in hydrogen bonding and SER153 and PHE379 are crucial for hydrophobic interactions of different modulators with PCSK9. In addition, structure based pharmacophore model was also built using model peptides as templates. The model comprises of four different pharmacophoric features including one hydrogen bond acceptor, one hydrophobic, one aromatic ring and one acceptor/donor features. Moreover, external validation of the model showed 80% model sensitivity and 83 % specificity towards the prediction of small molecular inhibitors against PCSK9. Thus, the results suggest that the current model can be used in virtual screening of new small molecular inhibitors against PCSK9 that can further validated through experimental protocols. Overall, the project could pave the way towards a new generation of drugs with a promise to help control hypercholesterolemia.