Abstract 1469 Biochemical screening of phytochemicals and identification of a potential inhibitor of SARS-CoV-2 Mpro and investigating its thermodynamic impact on the structural stability
Bibliographic record
Abstract
Due to the rise of antibiotic resistance in bacterial pathogens, there remains a large unmet need for novel therapeutic antibiotics to treat infections.Novel molecules with diverse structures that target different cellular machinery are of high importance as the majority of clinical antibiotics rely on inhibiting the same targets and make use of similar chemical scaffolds, which are susceptible to resistance.Promising research has shown that the bacterial ClpP protease, involved in protein homeostasis, is a viable target for antibiotic drug development.A previous chemical screen from our group has identified novel scaffolds that dysregulate the protease and were termed Activators of Self-Compartmentalized Proteases (ACPs) due to their ability to cause the nonspecific degradation of essential cellular housekeeping proteins, ultimately resulting in cell death.Co-crystal structure data of compound-ClpP complexes suggested that ACPs adopt two configurations in the binding site.A new class of ACP compounds has been developed that leverages a phosphine oxide moiety connecting the two aryl groups to adopt both configurations in the binding pocket.Using this strategy, novel derivatives were synthesized in the initial medicinal chemistry panel, expanding the chemical space of the analogs.The analogs were then screened for activity against ClpP, and hits were prioritized in subsequent biological assays.Lastly, activity results and co-crystal structures validate the structure-based approach to drug discovery as efficacy was improved and the binding conformation
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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 | 0.001 | 0.001 |
| 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 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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".