Discovery of a Novel Antimicrobial Agent by the Virtual Screening of a Library of Small Molecules

Abstract

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.

Evaluation of novel compounds as anti-bacterial or anti-virulence agents

“…In addition, compound 24 has satisfactory in silico pharmacokinetic properties and no cytotoxicity in two human cell lines. Further studies should be conducted to determine ClpP inhibitory potential and to validate the drug target ( Dighe et al., 2021 ).…”

“…Of the five selected hits, the antipsychotic pimozide provided the most promising experimental results in terms of pyocyanin production, swarming motility and biofilm formation. A recent study by Dighe et al (2021) presented the discovery of novel antimicrobial agents using a virtual screening approach based on a combination of docking and pharmacophore methods. They searched the CoCoCo database, which contains 1.4 million compounds, for new ClpP inhibitors (proteolytic subunit of caseinolytic protease).…”

“…In addition, compound 24 has satisfactory in silico pharmacokinetic properties and no cytotoxicity in two human cell lines. Further studies should be conducted to determine ClpP inhibitory potential and to validate the drug target (Dighe et al, 2021). Molecular docking studies were also carried out to verify and rationalize anti-bacterial properties of some synthesized compounds with promising MIC and MBC values indicating on possible structural modification for achieving better anti-bacterial activity.…”