A CoMSIA study to design antagonist ligands for the LuxS protein

The Impairment of Methyl Metabolism From luxS Mutation of Streptococcus mutans

“…Then SAH is converted into homocysteine (HCY) through a two-step process. SAH uses the enzyme Pfs to generate S-ribosyl-homocysteine, then converted into homocysteine (HCY) by the enzyme LuxS (Díaz et al, 2014 ). For bacteria without LuxS/Pfs pathway, including Pseudomonas aeruginosa , S-adenosyl-L-homocysteine hydrolase (SahH) encoded by sahH is used to complete the AMC (Cataldi et al, 2009 ; Fernandez-Sanchez et al, 2009 ).…”

Exploring interfacial dynamics in homodimeric S-ribosylhomocysteine lyase (LuxS) from Vibrio cholerae through molecular dynamics simulations

“…The difference in the inhibition potential of the two ligands towards the enzyme demonstrates also that the RHC inhibitor has low potency compared to KRI inhibitor as deduced from the respective experimental K i value of 4.2 and 0.37 μM for the RHC and KRI inhibitor towards the LuxS enzyme. 43 Still the difference in the free energy data obtained via TI is approximately 10 times lower than the experimental binding constant for the two ligands, which could be inferred as the involvement of different coordinating atoms of the RHC and KRI inhibitors towards the metal ion. The coordination bonds between the inhibitors and the metal ion were treated classically by applying distance restraint during MD simulations that can not fully account the metal–ligand contribution in the free energy estimation, however the energy data are encouraging that provides information on the relative binding potential of the two ligands – the KRI inhibitor being more potent compared to RHC.…”

“…The ligand selected for the enzyme–inhibitor complex was a substrate analogue, RHC that was modelled by matching coordinates with an available co-crystallized ligand reported in the protein databank (PDB ID: ), 35 and the ligand was further modified according to the reported chemical structure of the RHC inhibitor. 43 According to this study, the RHC inhibitor was reported to undergo a tautomerization reaction between its active aldehydic and the associated inactive hemiacetal form, and therefore, the ligand was modified in its active aldehydic form for the manual docking. 25,50 Another more potent inhibitor of LuxS, KRI was also modelled according to the study carried out by Vivas-Reyes and coworkers.…”

“…25,50 Another more potent inhibitor of LuxS, KRI was also modelled according to the study carried out by Vivas-Reyes and coworkers. 43 Moreover, a constraining bond between the divalent iron and the oxygen atoms of RHC and KRI was constructed to form the enzyme-inhibitor complexes of LuxS, since the inhibitors were reported to be form complexes by coordinating to the metal ion by replacing the water molecule, thus occupying the fourth coordination site of the metallocenter in LuxS.…”

“…Another study based on the comparative molecular similarity index analysis (COMSIA) was applied to verify the relative inhibition potential of twenty substrate analogs of ribosylhomocysteine (RHC) and other non-substrate analogs (KRI) but the study was not able to provide insights into the stability of the formed complexes at the atomistic level. 43 Later, detailed information on the structural and dynamical properties of the monomeric LuxS enzyme complexed with the most potent RHC derivative was obtained by applying all-atom MD simulation using newly constructed force-field parameters for the iron metallocenter. 44 The previous MD study provided detailed insight not only on the structural and dynamical properties of the enzyme and its complex with RHC inhibitor, but also revealed how the inhibitor binds to the LuxS active site.…”