Novel compounds with potential inhibitory activity of PCSK9 screened by virtual screening

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are used to dyslipidemic therapy for patients with intolerance and/or resistance to statins. However, PCSK9 inhibitors have high cost-effectiveness [1]. We used virtual screening (VS) strategy to search compounds against PCSK9. The VS of ~70 million compounds (Molecules, ZINC15 and Enamine databases) was performed using a PCSK9 crystal structure [2], and four compounds were selected by docking (cutoff ΔG <-3.86 kcal/mol). Molecular dynamics studies observed complementarity of these ligands with PCSK9 due to frequencies of interactions (>50%) during the simulations (200 ns). The ligands LBMAD04 and LBMAD05 interact by a hydrogen bond with Glu159 (>90%) along with the simulations and PCA analysis showed the difference in motion distributions between apostructure and complexes, suggesting the inhibitory state by the compounds. These results suggest that molecular modeling strategy is suitable for searching novel potential inhibitors of PCSK9 activity to be evaluated by in vitro studies.