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

The greatest risk factor for the onset of atherosclerotic cardiovascular disease (ASCVD) events is elevated low-density lipoprotein cholesterol (LDL-C).1,2 The evidence for a link between hypercholesterolemia and the risk of ASCVD has led to the development of various guidelines and evidence-based recommendations for lowering lipid levels. These guidelines have changed throughout time to stress lower levels of plasma LDL cholesterol (LDLC) and non-HDL cholesterol (non-HDLC).3,4 Familial hypercholesterolemia (FH) is an autosomal dominant genetic metabolic disorder defined by severely elevated blood LDL-C and other symptoms, including xanthomas and a history of premature coronary artery disease (CAD).5 Because the frequency of CAD is exceptionally high in FH patients and the onset is 15-20 years earlier than average, early identification, and therapy to prevent or postpone the development of atherosclerosis are essential. According to various studies, FH heterozygotes are found in 1 in 250-300 people, and even 10% of individuals with acute coronary syndrome may have FH.6,7 FH is thus one of the most important underlying disorders of CAD from the standpoint of public health.8

Despite the notable effectiveness of statin therapy, there are still considerable deficiencies in the management of hypercholesterolemia and, thus, many people on statin therapy still develop atherosclerosis. Due to severe hypercholesterolemia or poor adherence to existing treatments, some patients have consistently elevated LDL-C levels. Newer, more effective lipid-modifying preparations may provide therapeutic advantages for these patients.9, 10, 11, 12, 13

The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) in 2003 opened up the possibility of filling some of the gaps in hypercholesterolemia therapy.14 PCSK9 consists of 692 aminoacids, with the signal peptide being residues 1-30. The remaining protein is usually split into 3 domains. The prodomain is made up of residues 31-152, the catalytic domain is made up of residues 153-454, and the C-terminal domain is made up of residues 455-692.15 It is critical to mention, however, that PCSK9 is also present in other organs.16 PCSK9 attaches to the epidermal growth factor-like repeat A (EGF-A) domain of nascent LDLR in the trans-Golgi apparatus and makes it suitable for lysosomal breakdown.17 PCSK9 binds to LDLR on the cell surface after being secreted by hepatocytes, forming the LDLR–PCSK9 complex. The endocytic recycling of LDLR for lysosomal breakdown is hampered by this complex.18,19 These 2 processes work together to diminish LDL-C influx and LDLR cell surface presentation in hepatocytes, resulting in higher circulating LDL-C levels.20 Gain-of-function mutations in the PCSK9 gene provoke phenotypical FH by reducing the number of LDL receptors (LDLRs) on the hepatocyte surface.21,22 PCSK9 dysfunction (including loss-of function mutations) has been linked to lower levels of plasma LDLC and a decreased risk of coronary heart disease (CHD) of 88 percent over 15 years of follow-up.23,24

Monoclonal antibodies that inhibit the formation of the PCSK9-LDLR complex, antisense oligonucleotides and small interfering RNA (siRNAs) that reduce PCSK9 gene expression, and synthetic proteins (adnectin) or high-binding affinity mimetic peptides (annexin A2) that bind to PCSK9 and inhibit its interaction with LDLR were all used to investigate the effect of PCSK9 inhibition. However, due to their status as biological products, these medicines could elicit several immune-mediated responses that can culminate in the generation of neutralizing antibodies and ensuing reduction in efficacy. Moreover, their administration is typically by injection, unlike the small molecules commonly administered orally, and the high costs of these therapeutic approaches make prior authorization difficult and may hinder long-term adherence. The development of small-molecule PCSK9 inhibitors, because of their high potential and low cost, has garnered much interest in recent years.25,26

Numerous drugs are produced through a series of randomized clinical studies that can be time-consuming, expensive, or fail to demonstrate high inhibition. The use of theoretical approaches as an alternative means for estimating chemical activity might reduce the likelihood of false negatives prior to any testing.27 Virtual screening is the notion of drug discovery based on a computational strategy for finding new lead compounds for medication development. Therefore in-silico approaches can represent a broad and promising approach to discovering a novel target protein with the prediction of its biological activity.28

There are 2 basic virtual screenings, including target-based (structure-based) and ligand-based screening.29 The target-based virtual screening is based on the biological target's 3-dimensional (3D) structure. In this approach, compounds in databases were docked against a protein target to find the best compounds that fit into the target's binding site.30,31 Another approach (ligand-based) is based on the knowledge of known active chemicals. These compounds were utilized to create a pharmacophore and Quantitative Structure-Activity Relationship (QSAR) models, which specify the structural features that a molecule must possess in order to bind to the target.32

In this current work, virtual screening tools were employed to explore a potent small-molecule PCSK9 inhibitor in compounds that are already being studied in clinical trials. Due to their having already passed initial safety studies, these drugs can be accelerated for use as PCSK9 inhibitors.

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