Identification of Potent Small-Molecule PCSK9 Inhibitors Based on Quantitative Structure-Activity Relationship, Pharmacophore Modeling, and Molecular Docking Procedure

Ali Mahmoudi, Alexandra E. Butler, Maciej Banach, Tannaz Jamialahmadi, Amirhossein Sahebkar

Research output: Contribution to journalReview articlepeer-review

3 Citations (Web of Science)

Abstract

The leading cause of atherosclerotic cardiovascular disease (ASCVD) is elevated low-density lipoprotein cholesterol (LDL-C). Proprotein convertase subtilisin/kexin type 9 (PCSK9) attaches to the domain of LDL receptor (LDLR), diminishing LDL-C influx and LDLR cell surface presentation in hepatocytes, resulting in higher circulating LDL-C levels. PCSK9 dysfunction has been linked to lower levels of plasma LDLC and a decreased risk of coronary heart disease (CHD). Herein, using virtual screening tools, we aimed to identify a potent small-molecule PCSK9 inhibitor in compounds that are currently being studied in clinical trials. We first performed chemical absorption, distribution, metabolism, excretion, and toxicity (ADMET) filtering of 9800 clinical trial compounds obtained from the ZINC 15 database using Lipinski's rule of 5 and achieved 3853 compounds. Two-dimensional (2D) quantitative structure-activity relationship (QSAR) was initiated by computing molecular descriptors and selecting important descriptors of 23 PCSK9 inhibitors. Multivariate calibration was performed with the partial least square regression (PLS) method with 18 compounds for training to design the QSAR model and 5 compounds for the test set to assess the model. The best latent variables (LV) (LV=6) with the lowest value of Root-Mean-Square Error of Cross-Validation (RMSECV) of 0.48 and leave-one-out cross-validation correlation coefficient (R2CV) = 0.83 were obtained for the QSAR model. The low RMSEC (0.21) with high R²cal (0.966) indicates the probability of fit between the experimental data and the calibration model. Using QSAR analysis of 3853 compounds, 2635 had a pIC501) were defined as active, whereas 9 (pIC50
Original languageEnglish
Article number101660
JournalCurrent Problems in Cardiology
Volume48
Issue number6
DOIs
Publication statusPublished - Jun 2023

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