Discovery of putative natural compounds inhibitor of the germinant spore receptor CspC in Clostridioides difficile infection: Gaining insights via In silico and bioinformatics approach

Abstract

A Gram-positive anaerobic bacillus known as Clostridioides difficile (C. difficile) present in the intestinal tract of humans is the causative organism for C. difficile infection (CDI). A prospective target for the therapy of CDI is the germinant spore receptor CspC, a key regulator of the germination mechanism. The detection of bile acids by CspC has been reported to initiate the germination and signaling pathways in CDI. Herein, we examined small molecule compounds with putative inhibitory efficacies on CspC using integrative computational modeling approach. Due to their higher binding affinities as compared to metronidazole (Reference drug), the computational analysis identified three compounds (Hesperetin, Galbanic acid, and Tomatidine) as potential therapeutics for the receptor target. At the end of the 100ns molecular dynamics simulation, the stability investigations revealed Tomatidine and Galbanic acid to be more stable compounds compared to other simulated natural compounds, including the reference drug (Metronidazole). They also exhibited acceptable drug-likeness and pharmacokinetic properties as determined by the Lipinski’s rule of five. Notwithstanding the results of our study, it is still too premature to conclude that the drug candidates are appropriate for use among CDI patients without substantial clinical and preclinical research.

Keywords

• Clostridioides difficile
• C. difficile infection
• Antimicrobial resistance
• ADMET
• Molecular docking
• Molecular dynamics simulation