Finding small molecular compounds to decrease trimethylamine oxide levels in atherosclerosis by virtual screening

Abstract

Abstract The intestinal microbial metabolite trimethylamine oxide (TMAO) affects the formation and development of atherosclerosis (AS). The design and development of an effective targeted drug to reduce serum TMAO levels may provide new avenues for inhibiting AS morbidity. Target genes that may elevate TMAO levels in patients with AS were explored using bioinformatics, virtual screening, and molecular dynamics (MD). We expected these genes to indicate potential TMAO inhibitors. Of these genes, hFMO3 was responsible for increasing TMAO levels. Four small-molecule compounds (SMC-1, SMC-2, SMC-3, and SMC-4) with the lowest binding energy and CGenFF penalty < 10 were connected to the main binding pocket of hFMO3 by hydrogen and/or cation–pi interactions. A 100 ns MD simulation showed that the four systems quickly reached equilibrium. The root mean square deviation of all four small-molecule compounds was less than 0.35 nm, that of the four ligand complexes was less than 0.40 nm, and the average deviations of each amino acid residue from the reference position over time did not differ. Molecular mechanics Poisson–Boltzmann surface area analyses showed that SMC-2, SMC-3, and SMC-4 bound very well to hFMO3, and the energy contribution of the key residues LEU40 and GLU32 was more remarkable in SMC-2, SMC-3, and SMC-4. These four small-molecule compounds may be useful as targeted drugs to reduce serum TMAO levels, inhibiting atherosclerosis formation.