In Vitro and In Silico Studies of Soluble Epoxide Hydrolase Inhibitors from the Roots of Lycopus lucidus

Abstract

Soluble epoxide hydrolase (sEH) is an enzyme that is considered a potential therapeutic target in human cardiovascular disease. Triterpenes (1–4) and phenylpropanoids (5–10) were isolated from Lycopus lucidus to obtain sEH inhibitors through various chromatographic purificationtechniques. The isolated compounds were evaluated for their inhibitory activity against sEH, and methyl rosmarinate (7), martynoside (8), dimethyl lithospermate (9) and 9″ methyl lithospermate (10) showed remarkable inhibitory activity, with the IC50 values ranging from 10.6 ± 3.2 to 35.7 ± 2.1 µM. Kinetic analysis of these compounds revealed that 7, 9 and 10 were competitive inhibitors bound to the active site, and 8 was the preferred mixed type inhibitor for allosteric sites. Additionally, molecular modeling has identified interacting catalytic residues and bindings between sEH and inhibitors. The results suggest that these compounds are potential candidates that can be used for further development in the prevention and treatment for cardiovascular risk.

Biomolecular Interactions and Inhibition Kinetics of Human Soluble Epoxide Hydrolase by Tetrapeptide YMSV

“…However, the small but notable changes to the V max of the enzyme (Table 1) suggest it to be a mixed-competitive inhibitor. This inhibition mode is similar to that reported for martynoside, a phenylpropanoid isolated from the root of Lycopus lucidus (Han et al, 2021).…”

“…Additional interactions between YMSV and side chains (Asn378A, Asn472A, Trp473A, Tyr383A, Tyr446A, Gln384A, Ile363A, Phe381A, Tyr343A, Met339A, Leu499A and Met503A), backbone amino acids (Pro364A), and backbone side chain residues (Pro371A and Met469A) were also observed (Figure 7a). Similarly, competitive inhibition was previously reported for methyl rosmarinate, dimethyl lithospermate and 9″ methyl lithospermate, with similar interacting amino acid residues in sEH as that of AUDA (Han et al, 2021). The binding affinity of YMSV at the active site of sEH was predicted to be −7.669 kcal.mol −1 .…”

“…Cv. Habanero (Kim et al, 2019), phenolic compounds from Vietnam's Passiflora edulis seeds (Cuong et al, 2019), anthraquinone and stilbene derivatives from Rheum undulatum (Jo et al, 2016), as well as triterpenes and phenylpropanoid derivatives from Lycopus lucidus roots (Han et al, 2021). However, these natural sEH inhibitors have poor pharmacokinetics properties, including low water solubility, absorption in the gastrointestinal tract, and bioaccessibility (Lee et al, 2020).…”

Molecular docking and ADMET studies of soluble epoxide hydrolase inhibitors from the leaves of Paederia foetida L.

“…Previously, EETs was proved to decrease inflammation and platelet aggregation and in general act to maintain vascular homeostasis [5]. However, the EETs are metabolized by sEH to form the responding dihydroxyeicosatrienoic acids [6] and in consequence, the reactions result in diminished cardioprotective effects of EETs. Therefore, it could be interesting to hypothesize that the use of sEH blockers, which prevent EETs degradation, is a promising pharmacological approach to effectively treat CVDs in the future.…”