article · RSC Advances
Squalene epoxidase (SQLE) is an essential enzyme in sterol biosynthesis and a recognised therapeutic target for addressing hypercholesterolaemia and fungal infections. This investigation evaluated six flavonoids for their inhibitory effects against SQLE using combined computational and experimental methods. Computational docking and molecular dynamics simulations showed that apigenin-7-O-glucoside, silibinin, and baicalin formed stable interactions with the enzyme binding site and exhibited high binding affinities. Subsequent in vitro assays confirmed their activity, demonstrating that apigenin-7-O-glucoside was the most potent inhibitor, followed closely by silibinin and baicalin. Enzyme kinetics established competitive inhibition for apigenin-7-O-glucoside and mixed inhibition for silibinin and baicalin. In addition, computational pharmacokinetic analyses suggested favourable drug-like properties, with silibinin displaying notably high bioavailability and lipophilicity. These findings support further preclinical exploration of these plant-derived compounds as potential therapeutic leads.
Squalene epoxidase is a vital target for treating high cholesterol and fungal infections. Identifying effective inhibitors from natural flavonoids offers potential starting points for new, alternative therapies. By combining computer simulations with laboratory validation, this research provides validated molecular candidates and mechanistic insights that can guide the design of future medications targeting sterol biosynthesis pathways.
This work identifies apigenin-7-O-glucoside, silibinin, and baicalin as potential lead compounds for pharmaceutical developers targeting hypercholesterolaemia or fungal infections. The research sits at an early discovery stage, having established in vitro efficacy, inhibition mechanisms, and predictive pharmacokinetic profiles. Real-world application would require formal preclinical testing, including in vivo safety and efficacy evaluations, before advancing toward clinical development.
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Squalene epoxidase (SQLE) is a crucial enzyme in the sterol biosynthesis pathway and a promising target for therapeutic intervention in hypercholesterolemia and fungal infections. This study evaluates the inhibitory potential of six flavonoids namely silibinin, baicalin, naringenin, chrysin, apigenin-7-O-glucoside, and isorhamnetin against SQLE using an integrative approach combining <i>in silico</i> and experimental methods. Molecular docking revealed that apigenin-7-O-glucoside, silibinin, and baicalin displayed the highest binding affinities (-10.7, -10.2, and -10.0 kcal mol<sup>-1</sup>, respectively) and robust interactions with the SQLE binding site. These findings were corroborated by 200 ns molecular dynamics (MD) simulations, which demonstrated stable binding trajectories, minimal structural fluctuations, a thermodynamically favored potential energy landscape (PEL) and favorable MM/PBSA binding free energies for three flavonoids. Experimental validation <i>via in vitro</i> inhibition assays confirmed the computational predictions, with apigenin-7-O-glucoside emerging as the most potent inhibitor (IC<sub>50</sub> = 1.74 ± 0.05 μM), followed by silibinin (IC<sub>50</sub> = 1.88 ± 0.28 μM) and baicalin (IC<sub>50</sub> = 2.50 ± 0.46 μM). Enzyme kinetics studies revealed distinct mechanisms of action: apigenin-7-O-glucoside exhibited competitive inhibition, while silibinin and baicalin showed mixed inhibition. Furthermore, <i>in silico</i> ADMET analysis indicated favorable pharmacokinetic and pharmacodynamic profiles for these flavonoids, with silibinin demonstrating particularly high bioavailability and lipophilicity. This study highlights apigenin-7-O-glucoside, silibinin, and baicalin as potent SQLE inhibitors with promising therapeutic potential. The congruence between <i>in silico</i> predictions and experimental results underscores the reliability of computational approaches in drug discovery, paving the way for future preclinical development of these compounds as novel SQLE-targeted therapeutics.
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DOI: 10.1039/d4ra09076d
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