A virtual screening approach based upon a combination of docking and pharmacophore methods was utilized on a library of 1.4 million molecules to identify novel antimicrobial agents, which may potentially act via inhibition of the caseinolytic protease. Using this method, compound 6 was found to be bactericidal against three staphylococcal species (minimum inhibitory concentration (MIC)=4-16 μg/mL). Further, subsequent structural optimization of 6 led to the identification of compound 24, which was shown to be the most potent analog within the series (MIC=4 μg/mL) and outperforming the antibiotic controls for two of the staphylococcal species. The newly discovered antimicrobial agent (24) demonstrated excellent in silico ADME properties and was non-toxic when tested on two human skin cell lines. As such, compound 24 has the potential for use as a lead molecule in the development of a novel class of antimicrobial agents.
Keywords: ClpP; Virtual screening; antimicrobial; docking.
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