A Novel Urease Inhibitor of Ruminal Microbiota Screened through Molecular Docking

Abstract

Inhibition of the urease activity of ruminal microbiota is not only beneficial for increasing dietary and endogenic urea-N utilization efficiency in ruminants but also might be applicable for the preservation of nitrogen fertilizer in soil and treatment of gastrointestinal and urinary tract infections caused by ureolytic bacteria. To discover urease inhibitors to efficiently target ruminal microbiota, the identified ruminal microbial metagenomic urease gene was used to construct a homology model to virtually screen urease inhibitors from the ChemDiv database by molecular docking. The GMQE and QMEAN values of the homology model were 0.85 and −0.37, respectively, indicating a good model quality. The inhibition effect of the screened urease inhibitor for ruminal urea degradation was assessed by ruminal microbial fermentation in vitro. The toxic effect of the candidate inhibitor was performed using gut Caco-2 cells in vitro. The results showed that compound 3-[1-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-1H-pyrrol-2-yl] propanoic acid (ChemDiv_ID: 6238-0047, IC50 = 65.86 μM) was found to be the most effective urease inhibitor among the candidate compounds. Compound 6238-0047 significantly lowered the amount of urea degradation and ammonia production in ruminal microbial fermentation. The 24 h degradation rate of compound 6238-0047 in ruminal microbial fermentation was 3.32%–16.00%. In addition, compound 6238-0047 (10–100 μM) had no significant adverse effect on the cell viability of Caco-2 cells. Molecular docking showed that compound 6238-0047 could interact with Asp359 in the active site and Cys318 in the flap region by the hydrogen bond and Pi-Alkyl interaction, respectively. Compound 6238-0047 could be used as a novel inhibitor for decreasing the urease activity of ruminal microbiota.

Identification of Potential TMPRSS2 Inhibitors for COVID-19 Treatment in Chinese Medicine by Computational Approaches and Surface Plasmon Resonance Technology

“…The QMEAN score function is a valuable tool which provides the evaluation based on the overall quality of the homology models . The QMEAN score of the modeled TMPS2 was −0.53 closing to zero, indicating a good agreement between the modeled structure and experimental structure . The Ramachandran plot is widely applied to identify the stereochemically feasible angles of protein model, validating the skeletal conformation of a protein structure. , The plot revealed that 99.3% of the AA residues of the built TMPS2 were in allowed regions, with 86.9% residues in the most favored region, and only 0.7% in the disallowed region (Figure S2).…”

Characterization and Mechanism of Linearized-Microcystinase Involved in Bacterial Degradation of Microcystins

“…Therefore, the linearized-microcystinase encoded by the linearized-microcystinase gene from bacterium YF1 may participate in degrading MC-LR ( Bourne et al, 2001 ). Purified enzymes were often used to study their functions and characteristics ( Zhang et al, 2020 ). Heterologously expressed MC-degrading proteins were very useful in investigating the biochemical pathways and subsequent MC derivatives.…”

Epiberberine: a potential rumen microbial urease inhibitor to reduce ammonia release screened by targeting UreG

“…The study of ruminal microbial fermentation consisted of a control group and 3 epiberberine treatment groups, each containing 70 mL fresh rumen fluid and 140 mL anaerobic medium (Zhang et al 2020c ). Epiberberine treatment groups with the final concentration of 2, 20, and 200 μM were pre-incubated in an anaerobic chamber at 39 °C for 15 min.…”