Finding inhibitors for PCSK9 using computational methods

PLoS One. 2021 Aug 5;16(8):e0255523. doi: 10.1371/journal.pone.0255523. eCollection 2021.

Abstract

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is one of the key targets for atherosclerosis drug development as its binding with low-density lipoprotein receptor leads to atherosclerosis. The protein-ligand interaction helps to understand the actual mechanism for the pharmacological action. This research aims to discover the best inhibitory candidates targeting PCSK9. To start with, reported ACE inhibitors were incorporated into pharmacophore designing using PharmaGist to produce pharmacophore models. Selected models were later screened against the ZINC database using ZINCPHARMER to define potential drug candidates that were docked with the target protein to understand their interactions. Molecular docking revealed the top 10 drug candidates against PCSK9, with binding energies ranging from -9.8 kcal·mol-1 to -8.2 kcal·mol-1, which were analyzed for their pharmacokinetic properties and oral bioavailability. Some compounds were identified as plant-derived compounds like (S)-canadine, hesperetin or labetalol (an antihypertensive drug). Molecular dynamics results showed that these substances formed stable protein-ligand complexes. (S)-canadine-PCSK9 complex was the most stable with the lowest RMSD. It was concluded that (S)-canadine may act as a potential inhibitor against atherosclerosis for the development of new PCSK9 inhibitory drugs in future in vitro research.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Catalytic Domain
  • Combinatorial Chemistry Techniques
  • Drug Design*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / isolation & purification*
  • High-Throughput Screening Assays / methods*
  • Humans
  • Models, Molecular
  • Molecular Docking Simulation*
  • PCSK9 Inhibitors*
  • Proprotein Convertase 9 / chemistry
  • Protein Conformation

Substances

  • Enzyme Inhibitors
  • PCSK9 Inhibitors
  • PCSK9 protein, human
  • Proprotein Convertase 9

Grants and funding

This study was supported partly by HEC, Pakistan and the University of Lodz, Poland, grant number 506/1136 (M.B.P). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.