Enzyme Kinetics and Molecular Docking Studies on Cytochrome 2B6, 2C19, 2E1, and 3A4 Activities by Sauchinone

Abstract

Sauchinone, an active lignan isolated from the aerial parts of Saururus chinensis (Saururaceae), exhibits anti-inflammatory, anti-obesity, anti-hyperglycemic, and anti-hepatic steatosis effects. As herb–drug interaction (HDI) through cytochrome P450s (CYPs)-mediated metabolism limits clinical application of herbs and drugs in combination, this study sought to explore the enzyme kinetics of sauchinone towards CYP inhibition in in vitro human liver microsomes (HLMs) and in vivo mice studies and computational molecular docking analysis. In in vitro HLMs, sauchinone reversibly inhibited CYP2B6, 2C19, 2E1, and 3A4 activities in non-competitive modes, showing inhibition constant (Ki) values of 14.3, 16.8, 41.7, and 6.84 μM, respectively. Also, sauchinone time-dependently inhibited CYP2B6, 2E1 and 3A4 activities in vitro HLMs. Molecular docking study showed that sauchinone could be bound to a few key amino acid residues in the active site of CYP2B6, 2C19, 2E1, and 3A4. When sibutramine, clopidogrel, or chlorzoxazone was co-administered with sauchinone to mice, the systemic exposure of each drug was increased compared to that without sauchinone, because sauchinone reduced the metabolic clearance of each drug. In conclusion, when sauchinone was co-treated with drugs metabolized via CYP2B6, 2C19, 2E1, or 3A4, sauchinone–drug interactions occurred because sauchinone inhibited the CYP-mediated metabolic activities.

Effects of saikosaponin‐d on CYP3A4 in HepaRG cell and protein‐ligand docking study

“…It has been reported that the amino acid residues of Phe57, Phe108, Ile120, Leu211, Phe241, Ile301, Phe304, Ile369, Leu373, Arg105, Leu364, Arg365, Leu366, Phe367, Pro368, Ala370, Met371, Arg372 and Glu374 in CYP3A4 played a key role in ligand binding 38‐44 . Another study suggested that Phe57, Arg105, Arg106, Phe108, Phe215, Met371, Arg372, Leu373, Glu374 and Arg375 were involved in interaction between sauchinone and CYP3A4 protein 45 . Figure 5 indicated that Hem508, Arg105 and Glu374 amino acid residues interacts with SSd via hydrogen bond interactions at a distance of 2.88Å, 3.13Å and 3.21Å, respectively, while Ser119 was bonded at the distance of 2.81 Å and 3.18 Å. Hydrophobic interaction between SSd and CYP3A4 was formed with Phe57, Phe215, Asp76, Gly481, Leu373, He369, Thr309, Leu482, Phe304, He301, He120, Phe108, Arg106, Phe213 and Arg372 residues and SSd was prone to bind to amino acid residues in the A chain of the CYP3A4 protein.…”

Computational Approaches in Preclinical Studies on Drug Discovery and Development

“…FKA shows obvious inhibition of different CYP isoforms, and subsequent inhibition experiments showed that CYP3A2 was the primary isoform contributing to the metabolism of FKA. Gong et al ( 2018 ) performed a molecular docking experiment to study the binding mode between sauchinone and CYPs. The results showed the interactions of sauchinone in the active site of CYP2B6, 2C19, 2E1, and 3A4.…”

β-Caryophyllene Ameliorates MSU-Induced Gouty Arthritis and Inflammation Through Inhibiting NLRP3 and NF-κB Signal Pathway: In Silico and In Vivo

“…During this process, the "lock-key" principle of ligand-receptor interaction and the principle of "induction fit" by computer pattern recognition and optimization techniques are adopted respectively (Lohning et al, 2017). According to a large number of studies, computer-aided drug screening has managed to seek the best molecule combination, which has achieved success in active botanical components virtual screening and drug targets discorvery (Wang et al, 2017;Gong et al, 2018;Zihad et al, 2018;Saikia and Bordoloi, 2019). In this case, with the development of bioinformatics technology, it has become possible to extract the differentially expressed genes for specific diseases from open databases when conducting comprehensive research (Liang et al, 2016).…”