Molecular interaction of a putative inhibitor with bacterial SHV, an enzyme associated with antibiotic resistance.

Tackling the ever-looming threat of antibiotic resistance remains a challenge for clinicians and microbiologists across the globe. Sulfhydryl variable (SHV) is a known bacterial enzyme associated with antibiotic resistance. The SHV enzyme has many variants. The present article describes identification and molecular interaction of a putative inhibitor with the bacterial SHV enzyme as a step towards novel antibacterial drug discovery. The MCULE-platform was used for screening a collection of 5 000 000 ligand molecules to evaluate their binding potential to the bacterial SHV-1 enzyme. Estimation of pharmacokinetic features was realized with the aid of the 'SWISS ADME' tool. Toxicity-checks were also performed. The docked complex of 'the top screened out ligand' and 'the bacterial SHV-1 protein' was subjected to molecular dynamics simulation of 101 ns. The obtained ligand molecule, 1,1'-(4H,8H-Bis[1,2,5]oxadiazolo[3,4-b:3',4'-e]pyrazine-4,8-diyl)diethanone, displayed the most favourable binding interactions with bacterial SHV-1. A total of 15 amino acid residues were found to hold the ligand in the binding site of SHV-1. Noticeably, 12 of the 15 residues were found as common to the binding residues of the reference (PDB ID: 4ZAM). The RMSD values plotted against the simulation time showed that nearby 11 ns, equilibrium was reached and, thenceforth, the 'SHV-1-Top ligand' complex remained typically stable. Starting from around 11 ns and straight to 101 ns, the backbone RMSD fluctuations were found to be confined inside a range of 1.0-1.6 Å. The ligand, 1,1'-(4H,8H-Bis[1,2,5]oxadiazolo[3,4-b:3',4'-e]pyrazine-4,8-diyl)diethanone, satisfied ADMET criteria. Furthermore, the practicability of the described 'SHV-1-Top ligand' complex was reinforced by a comprehensive molecular dynamics simulation of 101 ns. This ligand hence can be considered a promising lead for antibiotic design against SHV-1 producing resistant bacteria, and thus warrants wet laboratory evaluation.