Decoding BCL6 Inhibitors: Computational Insights into the Impact of Water Networks on Potency
Bibliographic record
Abstract
Water molecules in the binding site can have a critical role in small molecule binding to proteins and are an important consideration in structure-based drug design. Water networks have additional complexity as displacing one water molecule has subsequent effects on the remaining network. Modification of a lead compound that disrupts a water network can have beneficial or detrimental impacts on potency and this outcome is impossible to determine experimentally without time-consuming synthesis of the new compound. Computational methods are ideally suited to study the interplay between ligand optimization and water displacement by predicting the effect of structural changes on both the activity of the compound and the stability of neighboring water molecules. We used Grand Canonical Monte Carlo (GCMC) simulations and alchemical free energy calculations to retrospectively study a series of B-cell Lymphoma 6 (BCL6) inhibitors that sequentially displaced water molecules from a network. The methods were used to rationalize the structure-activity relationship of the compounds by quantifying the individual contributions to the binding affinity from the changes in the water network and new interactions with the protein. GCMC simulations are well-suited for studying water networks in the binding site and were able to reproduce 94% of the experimentally observed water sites from the crystal structures in a subpocket of BCL6. Using the BCL6 project as an example, we show the power of these computational methods to study water networks and how they can provide insights that are able to guide drug discovery projects.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.003 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| 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 source (direct Gemma or distilled Codex), 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".