IN-SILICO IDENTIFICATION OF NEWER POTENTIAL PROPROTEIN CONVERTASE SUBSTILSIN/KEXIN TYPE 9 INHIBITORS AS POTENT ANTI-HYPERLIPIDEMIC AGENTS

IN-SILICO IDENTIFICATION OF NEWER POTENTIAL PROPROTEIN CONVERTASE SUBSTILSIN/KEXIN TYPE 9 INHIBITORS AS POTENT ANTI-HYPERLIPIDEMIC AGENTS

Priyadarsini * and V. Dinesh Kumar

Department of Pharmaceutical Chemistry, College of Pharmacy, Madras Medical College, Park Town, Chennai, Tamil Nadu, India.

ABSTRACT: Hyperlipidemia is a term that encompasses various genetic and acquired disorders that describe elevated lipid levels within the human body. The present study aims to design newer potent PCSK9 Inhibitors to treat hyperlipidemia. In the current study, pharmacophoric features like one hydrogen bond acceptor, one hydrogen bond donor, and one aromatic ring were used to construct a virtual library of ligands. A virtual library consists of 150 ligands containing substituted heterocycles like Imidazole, Thiazole, Oxadiazole, thiadiazole, oxazole, Benzthiazole, Amino triazole, Benzoxazole, Pyrimidine, and Pyrrole. The binding mechanism of newly designed ligands with target enzyme PCSK9 was studied using Autodock 4.2.6. Docking studies show that Lig7, Lig15, Lig34, Lig49, and Lig103 were highly active hits, and nearly 90 designed ligands were found to moderately inhibit PCSK9 enzyme, which is proven to be effective hits. When all the 150designed ligands were further subjected to drug-likeliness properties using software like Molinspiration, Osiris property Explorer all ligands were found to possess drug-likeliness properties.

Keywords: Hyperlipidemia, PCSK9 inhibitors, Molecular docking studies, ADMET properties

INTRODUCTION: Hyperlipidemia is a systemic disease that is characterized by elevated lipid levels in the blood, including total cholesterol (TC), total glyceride (TG), low-density lipoprotein cholesterol (LDL-c), and so on ¹. Hyperlipidemia is classified into a primary and a secondary type, which indicates the complexities associated with the disease. The primary diseases may be treated by using anti-hyperlipidemic drugs, but the secondary originating from diabetes hypothyroidism demands the treatment of the original disease rather than hyperlipidemia ².

It is an important risk factor leading to fatty liver, cardiovascular diseases, and atherosclerosis (increased plasma level of low-density lipoprotein) and has become the first killer of human health ³. Numerous epidemiological studies show that pharmacological lowering of LDL significantly reduces cardiovascular events. Currently, many drugs are commercially available to lower TC and LDL but have serious side effects such as myopathy, muscle pains, and rhabdomyolysis ⁴.

Hence, developing a new agent with fewer side effects is needed. Proprotein convertase substilsin/kexin 9 (PCSK9) plays a crucial role in regulating circulating levels of LDL-c as a consequence of its ability to inhibit LDL receptor recycling in the liver ⁵. Loss of functional variants in the PCSK9 gene results in low LDL-c levels and is associated with reduced cardiovascular risk.

The study's main aim is to identify novel, safe, and effective anti-hyperlipidemic agents with good predicted capability to inhibit the Proprotein convertase subsilsin/kexin type 9 (PCSK9) using a computational drug designing approach.

MATERIALS AND METHODS:

Selection of Target: The targets creating the greatest enthusiasm at this time for treating hyperlipidemia include HMG Co-A reductase, ATP Citrate lyase, Apolipoprotein B, PCSK9, Angiopoietin-like3, Sterol regulatory element binding protein and PPAR-α activators ⁶.

Based on the literature review, Proprotein convertase substilsin/kexin type9 was chosen as the effective target in discovering newer anti-hyperlipidemic drugs ⁷.

Some of the recent and efficient PDB enzyme targets for treating hyperlipidemia with lower resolution values were selected.

Some of the selected receptors listed below highlighted the best PDB target selected for the current study.

TABLE 1: LIST OF PDB FOR PCSK9 TARGET FOR HYPERLIPIDEMIA

Pharmacophore Identification: A Pharmacophore is defined as “a set of structural features in a molecule that is recognized at a receptor site and is responsible for that molecule’s biological activity”. Pharmacophore modeling correlates the biological activity with the spatial arrangement of various features in set of active analogues.

When reviewing the efficient journals and research articles, the pharmacophore model consisting of one hydrogen bond acceptor (HBA), one hydrogen bond donor (HBD), and aromatic ring features was identified as the best model for designing PCSK9 inhibitor ⁸.

Database Screening: Based on the above quoted literature facts in designing potent PCSK9 inhibitors, the target screening library was designed by using molecular fragments from a relatively narrow and low molecular weight, selected diversity at both the putative “scaffold” core.

The analogue library was generated by modifying the respective functional groups with sterically and conformation ally allowed substituents using the reagent database and a combinatorial design model.

Virtual Scaffold Library: A virtual library consisting of newly designed 150 lead molecules as potent PCSK9 inhibitors was generated based on the knowledge of the binding interaction of the ligand with the protein and the common features necessary for the molecule's biological activity.

Lead Optimization:

Molecular Docking Studies: In the current molecular simulation study, Autodock 4.2.6 software was used to predict the binding energy of all the designed ligands with PCSK9 protein ⁹.

Drug likeliness Screening: Drug likeliness is a qualitative concept indicated by the molecular properties that affect absorption, distribution, metabolism, excretion, and toxicity (ADMET) of a compound ¹⁰.

Drug likeliness properties of the newly designed PCSK9 inhibitors were determined by employing Online software like Molinspiration, and Osiris property explorer, and the results were tabulated.

RESULTS AND DISCUSSION: In search of new and potent PCSK9 inhibitors as anti-hyperlipidemic agents, a virtual scaffold library of 150 molecules was constructed using ChemDrawsoftware by reviewing efficient articles and journals and based on features like HBD, HBA, and Aromatic ring.

TABLE 2: MOLECULAR FRAGMENTS USED IN CONSTRUCTION OF LIBRARY OF PCSK9 INHIBITOR

Virtual Scaffold Library of Ligands:

Docking Results: Docking studies were performed on all the newly designed PCSK9 inhibitors using Autodock4.2.6 to identify which ligand interacts better with the target protein.

Based on the docking scores, all the newly designed ligands were categorized as highly active, moderately active, and low active hits as below.

TABLE 3: DOCKING SCORES OF DESIGNED LIGANDS

TABLE 4: DOCKING RESULTS OF PCSK9 INHIBITORS USING AUTODOCK4.2.6

Drug Likeliness Screening:

TABLE 5: DRUG LIKELINESS REPORTS FOR PCSK9 INHIBITORS

Toxicity:

 CONCLUSION: In-silico identification approaches have revealed that all newly designed PCSK9 inhibitors have a crucial role in suppressing LDL-cholesterol concentrations and thus can be used for the treatment of hyperlipidemia. By reviewing the literature, the important chemical features which can inhibit the activity of PCSK9 were identified, and 3D structural queries of newer 150 heterocyclic ligands were screened to retrieve new potent PCSK9inhibitors. Lipinski’s rule of five and ADMET properties screening assisted us in discarding the non–drug-like compounds. Furthermore, the screened drug-like compounds was identified and was further subjected to molecular docking study. Hence, we propose that the final hit compounds like Lig7, Lig15, Lig 17, Lig18, Lig20, Lig34, Lig49, Lig91, Lig101, Lig103, Lig131, Lig133, Lig137, Lig149 as a possible virtual leads to design novel PCSK9 inhibitors which can be synthesized and screened for in-vitro and in-vivo anti-hyperlipidemic activity in future.

ACKNOWLEDGEMENT: We thank Madras Medical College for providing all the facilities to carry out research work.

CONFLICTS OF INTEREST: The authors declare no conflict of interest.

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    How to cite this article:

    Priyadarsini R and Kumar VD: In-silico identification of newer potential proprotein convertase substilsin/kexin type 9 inhibitors as potent antihyperlipidemic agents. Int J Pharm Sci & Res 2022; 13(12): 5152-68. doi: 10.13040/IJPSR.0975-8232.13(12).5152-68.

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