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Published on: January 4, 2018
Combined computational and pharmacological approach reveals Citrullus colocynthis as a natural PCSK9 inhibitor in
Hafiz Abdul Sattar Hashmi1, Hafiz Muhammad Asif1, Khalil Ahmad1
1University College of Conventional Medicine, Faculty of Medicine & Allied Health Sciences, the Islamia University of Bahawalpur, Pakistan.
Abstract:
This study evaluated the therapeutic effects of Citrullus colocynthis seed extract (CCSE) on PCSK9 expression in a high-fat diet (HFD)-induced insulin resistance (IR) model in Wistar rats. Fifteen phytoconstituents from CCSE were screened for drug-likeness using SwissADME and docked against PCSK9 (PDB ID: 6U26). In vivo, 30 HFD-induced-IR rats were divided into five groups: one control (saline) and four treatment groups received CCSE (100,200,300,400 mg/kg) for 28 days. Hepatic PCSK9 mRNA expression was analyzed by qRT-PCR, with relative fold changes. Data were statistically evaluated by ANOVA. In-silico analysis demonstrated all selected compounds complied with Lipinski's Rule of Five, indicated favorable oral bioavailability. Topological polar surface area (TPSA: 9.23-55.38 Ų) and number of rotatable bonds (NRB >10) further supported their drug-like properties. Strong binding affinities were of compounds Cyclopropane carboxylic acid and 2,4-di-tert-butylphenol (-7.4 and -5.5 kcal/mol) to PCSK9. In-vivo results showed that CCSE significantly downregulated hepatic PCSK9 mRNA expression at a dose of 300mg & 400mg/kg (p < 0.05 vs. control), with the highest reduction (3.2-fold) observed at the 400 mg/kg dose. CCSE significantly downregulated hepatic PCSK9 mRNA expression and confirmed through both in-silico and In-vivo approaches. This suggests its potential as a natural therapeutic agent for managing metabolic disorders.
Insights
Citrullus colocynthis seed extract (CCSE) effectively lowers PCSK9 expression in rats with high-fat diet-induced insulin resistance. This natural compound shows promise for managing metabolic disorders.
Area of Science:
- Pharmacology
- Metabolic Disorders
- Natural Products
Background:
- High-fat diet (HFD) induces insulin resistance (IR), a metabolic disorder.
- Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a role in lipid metabolism and cardiovascular risk.
- Novel therapeutic strategies are needed to manage HFD-induced IR and associated metabolic dysregulation.
Purpose of the Study:
- To evaluate the therapeutic effects of Citrullus colocynthis seed extract (CCSE) on PCSK9 expression in an HFD-induced IR rat model.
- To investigate the in-silico and in-vivo efficacy of CCSE against PCSK9.
Main Methods:
- In-silico screening of CCSE phytoconstituents for drug-likeness and PCSK9 binding affinity.
- Induction of IR in Wistar rats using a high-fat diet.
- Administration of varying CCSE doses (100-400 mg/kg) to HFD-induced IR rats for 28 days.
- Quantification of hepatic PCSK9 mRNA expression using qRT-PCR.
Main Results:
- In-silico analysis confirmed favorable drug-like properties and binding affinities of CCSE compounds to PCSK9.
- CCSE significantly downregulated hepatic PCSK9 mRNA expression at doses of 300 and 400 mg/kg (p < 0.05).
- A maximum 3.2-fold reduction in PCSK9 mRNA was observed at the 400 mg/kg CCSE dose.
Conclusions:
- CCSE demonstrates significant therapeutic potential in downregulating hepatic PCSK9 expression in an HFD-induced IR model.
- Both in-silico and in-vivo findings support CCSE's efficacy.
- CCSE may serve as a natural therapeutic agent for managing metabolic disorders.
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