Polypharmacology prediction: the long road toward comprehensively anticipating small-molecule selectivity to de-risk drug discovery
Bibliographic record
Abstract
INTRODUCTION: Small molecules often bind to multiple targets, a behavior termed polypharmacology. Anticipating polypharmacology is essential for drug discovery since unknown off-targets can modulate safety and efficacy - profoundly affecting drug discovery success. Unfortunately, experimental methods to assess selectivity present significant limitations and drugs still fail in the clinic due to unanticipated off-targets. Computational methods are a cost-effective, complementary approach to predict polypharmacology. AREAS COVERED: This review aims to provide a comprehensive overview of the state of polypharmacology prediction and discuss its strengths and limitations, covering both classical cheminformatics methods and bioinformatic approaches. The authors review available data sources, paying close attention to their different coverage. The authors then discuss major algorithms grouped by the types of data that they exploit using selected examples. EXPERT OPINION: Polypharmacology prediction has made impressive progress over the last decades and contributed to identify many off-targets. However, data incompleteness currently limits most approaches to comprehensively predict selectivity. Moreover, our limited agreement on model assessment challenges the identification of the best algorithms - which at present show modest performance in prospective real-world applications. Despite these limitations, the exponential increase of multidisciplinary Big Data and AI hold much potential to better polypharmacology prediction and de-risk drug discovery.
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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 | 0.002 | 0.004 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.002 | 0.003 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.002 | 0.002 |
| Open science | 0.002 | 0.001 |
| Research integrity | 0.002 | 0.003 |
| Insufficient payload (model declined to judge) | 0.004 | 0.003 |
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".