Comprehensive computational study in the identification of novel potential cholesterol lowering agents targeting proprotein convertase subtilisin/kexin type 9

Abstract

The enzymatic target proprotein convertase subtilisin/kexin type 9 (PCSK9) is critically involved in the regulation of the lipoprotein metabolism leading to the degradation of low-density lipoprotein receptors (LDLRs) upon binding. Drugs that lower LDL cholesterol (LDL-C) through the inhibition of PCSK9 are useful in the management of hypercholesterolemia which greatly reduces the associated risk of atherosclerotic cardiovascular disease (CVD). In 2015, anti-PCSK9 monoclonal antibodies (mAbs), alirocumab and evolocumab were approved but owing to their high costs their prior authorization practices were impeded, reducing their long-term adherence. This has drawn considerable attention for the development of small-molecule PCSK9 inhibitors. In this research work, novel and diverse molecules with affinity towards PCSK9 thereby having ability to lower cholesterol. A hierarchical multistep docking was implemented to identify small molecules from chemical libraries with a score cutoff −8.00 kcal/mol, thereby weeding all the non-potential molecules. A set of seven representative molecules Z1139749023, Z1142698190, Z2242867634, Z2242893449, Z2242894417, Z2242909019, and Z2242914794 have been identified from a comprehensive computational study which included assessment of pharmacokinetics and toxicity profiles and binding interactions along with in-depth analysis of structural dynamics and integrity using prolong molecular dynamics (MD) simulation (in-duplicate). Furthermore the binding affinity of these PCSK9 inhibitory candidates molecules was ascertained over 1000 trajectory frames using MM-GBSA calculations. The molecules reported herein are propitious candidates for further development through necessary experimental considerations.

Communicated by Ramaswamy H. Sarma

Keywords:

• Cholesterol lowering agents
• proprotein convertase subtilisin/kexin type 9
• structure-based virtual screening
• molecular dynamics simulations
• MM-GBSA

Acknowledgement

RRSP gratefully acknowledges NVIDIA Corporation with the generous donation of the Titan V GPU, DSTE, Goa for the computational facility.

Authors’ Contributions

DM was involved in the investigation, data curation, formal analysis, writing original draft, review and editing; RRSP contributed to the conceptualization, review and editing; VNT was involved in conceptualization, review, editing and supervision.

Disclosure Statement

The authors declare no conflict of interest.

Consent for Publication

All authors provide their consent for the publication of this research work.

Funding

The research conducted herein is supported by the Department of Science, Technology and Environment, Goa State, India, vide Sanction Order vide L. No. 8-256-2014/STE-DIR/2013 dated 26.04.2018.

Data availability statement

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.