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Discovering Novel Drug Targets in Clostridioides difficile and Proposing FtsZ Inhibitors via Structure-Based Virtual
Mohammad Sholeh1, Masoumeh Beig1, Safoura Moradkasani1
1Department of Bacteriology, Pasteur Institute of Iran, Tehran, Iran.
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.
Insights
Novel drug targets were identified for Clostridioides difficile infections. The FtsZ protein was found to be a promising target, with fasamycin C and formicamycin D showing potential as effective inhibitors against antibiotic-resistant strains.
Area of Science:
- Computational drug discovery
- Microbiology
- Structural biology
Background:
- Clostridioides difficile (C. diff) is a significant healthcare-associated pathogen.
- Rising antibiotic resistance necessitates novel therapeutic strategies.
- Older adults are particularly vulnerable to severe C. diff infections.
Purpose of the Study:
- To identify novel drug targets and inhibitors for Clostridioides difficile.
- To computationally screen for compounds effective against C. diff.
- To address the challenge of antibiotic resistance in C. diff infections.
Main Methods:
- In silico identification of C. diff drug targets using bioinformatics tools (EDGAR, PSORTb).
- Structure-based virtual screening of compounds against the FtsZ protein using molecular docking and dynamics simulations.
- Evaluation of binding affinity, drug-likeness (Lipinski's Rule of Five), and ADMET properties.
Main Results:
- Six potential drug targets were identified, including FtsZ.
- Virtual screening identified 27 high-affinity ligands for FtsZ.
- Fasamycin C and formicamycin D demonstrated strong binding affinity and favorable drug-like properties.
- Molecular dynamics simulations confirmed the stability of FtsZ-ligand complexes.
Conclusions:
- FtsZ is a promising drug target for C. diff.
- Fasamycin C and formicamycin D are potential inhibitors for C. diff infections.
- Computational methods accelerate antimicrobial drug discovery for resistant pathogens.
- Further in vitro and in vivo validation is required.
