INTRODUCTION: Clostridioides difficile is a major healthcare-associated pathogen causing severe diarrhea and recurrent infections, particularly in older adults. With rising antibiotic resistance, identifying novel drug targets and inhibitors is crucial for effective therapeutic intervention. METHODS: A two-phase in silico approach identified potential drug targets from C. difficile strain 630. Complete protein sequences were retrieved from NCBI, with high-prevalence proteins identified using EDGAR and essential cytoplasmic proteins determined through PSORTb. Proteins homologous to the human proteome and gut microbiota were excluded. The filamenting temperature-sensitive mutant Z (FtsZ) protein was selected for structure-based virtual screening using the AlphaFold-generated model. Molecular docking simulations were performed on StreptomeDB compounds using AutoDock Vina, followed by molecular dynamics simulations. Binding affinity, Lipinski's Rule of Five compliance, and ADMET properties were evaluated. RESULTS: Six promising drug targets were identified: nusG, nusA, accB, argB, ftsZ, and aroE. Virtual screening against FtsZ revealed 27 high-affinity ligands, with fasamycin C and formicamycin D demonstrating favorable profiles. Molecular dynamics simulations confirmed FtsZ-ligand complex stability. DISCUSSION: Identification of FtsZ as a drug target with fasamycin C and formicamycin D as promising inhibitors offers potential solutions for C. difficile infections amid escalating antibiotic resistance. This computational approach enhances antimicrobial drug discovery efficiency. CONCLUSION: This study identified six drug targets for C. difficile, with FtsZ emerging as a promising therapeutic candidate. Fasamycin C and formicamycin D exhibited strong binding affinity and favorable drug-like properties. In vitro and in vivo validation is essential to translate these findings into viable therapeutic options.
Sholeh et al. (2026) studied this question.