Phase 8h-lite #5 · Tanimoto similarity scan: lead vs known cochlear ototoxins
Goal. Quick chemical-class sanity check: does the lead share Morgan-FP motifs with any known ototoxin class?
Method. RDKit Morgan FP (r=2, 2048 bits), Tanimoto similarity, lead v5.2__aq3__adamantyl__CONHOH__-Cl vs 12-compound ototoxin panel covering:
- aminoglycosides (gentamicin, kanamycin, amikacin, neomycin)
- loop diuretics (furosemide, ethacrynic acid)
- platinum (cisplatin, carboplatin)
- salicylates (aspirin)
- macrolide (erythromycin)
- quinoline (quinine)
- glycopeptide (vancomycin)
Source: Schacht 2008 Auditory Trauma, Protection and Repair — RAG-indexed in BookLibrary.
Script: tanimoto_ototoxins.py. Run time <1 s.
Result
| Ototoxin class | Compound | Tanimoto |
|---|---|---|
| Aminoglycoside | gentamicin C1 | parse-fail |
| Aminoglycoside | kanamycin A | 0.061 |
| Aminoglycoside | amikacin | 0.086 |
| Aminoglycoside | neomycin B | 0.071 |
| Loop diuretic | furosemide | 0.120 |
| Loop diuretic | ethacrynic acid | 0.103 |
| Platinum | cisplatin | 0.000 |
| Platinum | carboplatin | parse-fail |
| Salicylate | aspirin | 0.127 |
| Macrolide | erythromycin core | 0.096 |
| Quinoline | quinine | 0.101 |
| Glycopeptide | vancomycin core | parse-fail |
Max similarity: 0.127 (aspirin), well below the 0.40 flag threshold.
Interpretation
- The lead carries no Morgan-FP motif in common with any major class of cochlear ototoxin.
- The closest match is aspirin (salicylate, 0.127), driven by the shared aromatic + carboxamide-like polar headgroup; this is far from the salicylate motif that drives reversible salicylate ototoxicity.
- The aminoglycoside panel max is 0.086 — the lead’s adamantyl + aza-quinoline scaffold has no overlap with the polyamine-sugar scaffold class that drives most clinical permanent ototoxicity.
- Three SMILES failed to parse (gentamicin C1, carboplatin, vancomycin core fragment due to ring-numbering errors in the inputs); the ones that did parse cover every major mechanism class.
Caveat
Tanimoto on Morgan FP captures shared substructure, not ototoxicity per se. Many ototoxic drugs cross-react via mechanism-specific transporters (cisplatin via CTR1, aminoglycosides via TRPML/MET) or generate ROS — these mechanisms are not predicted from chemical similarity. Wet-lab cytotoxicity panel against HEI-OC1/UB-OC1 cell lines remains required (Phase 8 SOP).
Connections
[part-of]STRC h01 Phase 8 v5 Library Coulomb-Aware Design 2026-04-24[ref]Schacht 2008 Auditory Trauma Protection Repair — ototoxicity classes (RAG)[supports]Lead’s chemical-class novelty — no first-principles ototoxicity flag