Structure-based virtual screening to identify inhibitors against Staphylococcus aureus MurD enzyme

• Published in: Structural chemistry Vol. 30; no. 6; pp. 2123 - 2133
• Main Authors: Azam, Mohammed Afzal, Jupudi, Srikanth
• Format: Journal Article
• Language: English
• Published: New York Springer US 01-12-2019; Springer Nature B.V
• Subjects: Antibacterial materials; Binding; Binding energy; Chemistry; Chemistry and Materials Science; Computer Applications in Chemistry; Computer simulation; Enzymes; Free energy; Malachite green; Molecular dynamics; Original Research; Pathogens; Penicillin; Physical Chemistry; Proteins; Screening; Solvation; Theoretical and Computational Chemistry; MD simulation; MurD enzyme; HTVS; ADMET predictions
• ISSN: 1040-0400; 1572-9001
• DOI: 10.1007/s11224-019-01330-z

The MurD enzyme of
Staphylococcus aureus
is an attractive drug target as it is essential and ubiquitous in bacteria but absent in mammalian cells. In the present study, we performed in silico high-throughput virtual screening with small molecule library of 1.60 million compounds to identify potential hits. We used
S. aureus
modeled MurD protein for this purpose and to find the best leads, dock complexes were further subjected to the extra-precision docking and binding free energy calculations by MM-GBSA approach. It is evident that van der Waals and Coulomb energy terms are major favorable contributors while electrostatic solvation energy term strongly disfavors the binding of ligands to the
S. aureus
MurD enzyme. The inhibitory activity of two selected virtual hits
H5
and
H10
was performed against
S. aureus
MurD enzyme using malachite green assay. In in vitro antibacterial screening, compound
H5
inhibited the growth of
S. aureus
NCIM 5021,
S. aureus
NCIM 5022, and methicillin-resistant
S. aureus
(MRSA strain 43300) at high concentrations while the other tested compound
H10
was inactive against all the tested strains. In order to validate the stability of inhibitor-protein complex, compound
H5
with the highest inhibitory against
S. aureus
MurD and lowest binding free energy was subjected to 30-ns molecular dynamics simulation. Further, ADMET predictions showed the favorable pharmacokinetic profile of compounds
H5
and
H10
.