First-Principles Modeling of Nitazoxanide Analogues as Prospective PFOR-Targeted Antibacterials

Area of Science:

• Biochemistry
• Medicinal Chemistry
• Computational Chemistry

Background:

• Pyruvate:ferredoxin oxidoreductase (PFOR) is a critical enzyme in anaerobic pathogens, representing a potential therapeutic target.
• Nitazoxanide is an established inhibitor of PFOR, serving as a benchmark for drug design.

Purpose of the Study:

• To decipher the molecular recognition code governing PFOR inhibition.
• To establish practical design rules for developing novel PFOR inhibitors with improved efficacy.

Main Methods:

• Density Functional Theory (DFT) calculations for electronic structure analysis.
• Cheminformatic Quantitative Structure-Activity Relationship (QSAR) metrics.
• Residue-resolved molecular docking simulations.

Main Results:

• A conserved binding triad involving hydrogen bonds to Thr-997 and Cys-840, a π-π stack with Phe-869, and a π-σ contact to Thr-997 was identified.
• Deacetylation of nitazoxanide to tizoxanide slightly reduced binding affinity.
• Strategic halogenation introduced a beneficial σ-hole interaction, enhancing binding affinity and pose geometry in novel analogues.

Conclusions:

• A minimal, testable recipe for PFOR inhibitor design involves retaining a phenolic donor, maintaining interactions with Thr-997/Cys-840 and Phe-869, and incorporating a calibrated halogen σ-hole.
• These design rules offer falsifiable predictions to surpass nitazoxanide's efficacy and guide future synthesis and validation efforts.