How Math Supercharges the Hunt for New Medicines
Imagine a world where a scraped knee could kill. This isn't dystopian fiction—antibiotic resistance is making it a reality. With 30 million lives potentially at stake by 2050 and no major new antibiotic classes in 30 years, scientists face a crushing challenge: test millions of compounds to find a handful that work 6 .
Traditional drug screening is like searching for a needle in a haystack—one straw at a time. Each well in a microplate tests just one compound, requiring thousands of plates and millions of dollars.
But what if each well could test dozens of compounds at once without confusion? Enter row-constrained supersaturated designs (SSDs)—a statistical powerhouse accelerating drug discovery from "impossible" to "achievable."
Picture a 1,536-well plate (smaller than your smartphone). Normally, you'd test 1,536 compounds—one per well. But SSDs flip this logic. By strategically assigning multiple compounds per well, they screen 10,000+ candidates in those same 1,536 wells. It's like solving a 10,000-piece puzzle with only 1,500 pieces 1 2 .
Biology sets a hard rule: each well can physically hold only a limited number of compounds (e.g., ≤ 20). Older pooling methods ignored this, causing false positives when too many compounds interacted. Row-constrained SSDs enforce this limit mathematically while maximizing information extraction 2 .
How do you untangle which compounds worked when wells contain mixtures? The secret is Lasso (Least Absolute Shrinkage and Selection Operator) regression. It identifies "active" compounds by:
Think of it as finding the loudest voices in a stadium crowd by muting whispers.
In 2024, researchers targeted New Delhi metallo-β-lactamase (NDM-1)—an enzyme that makes bacteria resistant to nearly all antibiotics. It's linked to 50% of COVID-19 secondary deaths 2 . Using row-constrained SSDs, they screened 15,360 compounds in just 1,536 wells—10x faster than traditional methods.
Generate an SSD matrix assigning 15,360 compounds (columns) to 1,536 wells (rows). Each well contains ≤ 15 compounds.
Load compounds into wells using robotic liquid handlers. Add NDM-1 enzyme and a fluorescent substrate.
Dim glow = enzyme inhibited. Apply Lasso regression to pinpoint which specific compounds caused the effect 2 .
The experiment identified three novel NDM-1 inhibitors missed by prior screens. One compound (C-8910) reduced bacterial survival by 99% at nanomolar concentrations. Crucially, SSD's low false-positive rate saved months of follow-up testing 2 4 .
| Method | Wells Used | Compounds | False Positives |
|---|---|---|---|
| Traditional | 15,360 | 15,360 | 5-10% |
| Pooled (poolHiTS) | 1,536 | 15,360 | 15-30% |
| SSD + Lasso | 1,536 | 15,360 | < 5% |
| Compound | Enzyme Inhibition | Kill Rate | New? |
|---|---|---|---|
| C-8910 | 98.2 ± 0.5% | 99.1% | Yes |
| C-4501 | 92.1 ± 1.2% | 95.3% | Yes |
| C-7622 | 88.7 ± 2.1% | 93.0% | Yes |
| Reagent/Tool | Function | Why Essential |
|---|---|---|
| Multiwell Plates | Micro-containers for reactions (96-1,536 wells) | Physical platform for compound pooling |
| Robotic Handlers | Precision liquid dispensers | Enables accurate mixing of 10+ compounds per well |
| Compound Libraries | Collections of drug candidates | Source of "haystack" molecules for screening |
| Lasso Algorithms | Statistical software (e.g., R, Python glmnet) | Decodes complex well data to identify active compounds |
| Fluorescent Reporters | Molecules that glow upon enzyme activity | Measures biological effect in real time |
Traditional pooling (e.g., poolHiTS) required upfront guesses about "hit rates" and produced irreproducible results. One study screened 300,000 compounds but missed key inhibitors due to high false positives 6 . SSDs need no such assumptions and work even when 99.9% of compounds are inert .
Row-constrained SSDs are being adapted for:
With AI integration, SSD predictions could soon prioritize "high-potential" compounds, cutting screening costs by 95%. As one researcher put it: "We're no longer throwing darts in the dark. Math lights up the board" 4 .
In the war against superbugs and untreatable diseases, row-constrained SSDs offer our smartest weapon yet—proving that sometimes, overcrowding is exactly what science needs.