Simulating New Fusidic Acid Derivatives to Target Gram‐Positive Bacteria by Using Computational Methods
Bibliographic record
Abstract
Abstract Gram‐positive bacteria represent a significant threat due to their resistance to conventional antibiotics. This study employs computational methods to investigate fusidic acid (FA) derivatives ( 1 – 24 ) as potential antibiotics against Gram‐positive bacteria. Techniques such as density functional theory calculations, molecular docking, and molecular dynamics simulations were utilized to evaluate ligand interactions with target proteins Staphylococcus aureus ( S. aureus ) elongation factor G ( fusA) (2XEX), fusidic acid resistance protein ( fusB ) (4ADN), and fusidic acid resistance protein ( fusC ) (2YB5), comparing them to established antibiotics (ceftobiprole, linezolid, vancomycin). Notably, ligand 16 demonstrated a remarkable binding affinity to the S. aureus elongation factor G protein (−8.7 kcal mol⁻¹), closely aligning with both in vitro and in vivo results and outperforming fusidic acid and reference drugs. In silico methods (SwissADME, AdmetSAR, Molinspiration, Molsoft) were used to assess pharmacokinetics and drug‐likeness. Molecular dynamics (MD) simulations confirmed superior S. aureus elongation factor G stability for ligands fusidic acid 1 , (Z)‐2‐((3R,4S,8S,9R,10S,11R,13S,14S,16S)‐16‐acetoxy‐3,11‐dihydroxy‐4,8,10,14‐tetramethylhexadecahydro‐17H‐cyclopenta[a]phenanthren‐17‐ylidene)‐5‐cyclohexylidene‐ pentanoic acid ( 14 ), (Z)‐2‐((3R,4S,8S,9R,10S,11R,13S, 14S,16S)‐16‐acetoxy‐3,11‐dihydroxy‐4,8,10,14‐tetramethylhexadecahydro‐17H‐cyclopenta[a]phenanthren‐17‐ylidene)‐5cyclohexylidenepentanoic acid ( 16 ), and (Z)‐2‐((3R,4S,8S,9R,10S,11R,13S,14S,16S)‐16‐acetoxy‐3,11‐dihydroxy‐4,8,10,14‐tetramethylhexadecahydro‐17H‐cyclopenta[a]phenanthren‐17‐ylidene)‐5‐cyclopentylidenepentanoic acid ( 17 ), with ligand 16 exhibiting exceptional stability across various temperatures, especially at human body temperature (310 K). Further molecular dynamics simulations of ligand 16 validated its robust stability and potential to disrupt S. aureus elongation factor G, supporting the docking results and showing strong consistency with in vitro and in vivo findings. Consequently, ligand 16 emerges as a promising candidate for further development as an anti‐Gram‐positive bacterial drug, pending validation through rigorous clinical trials.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".