Phase 8h-lite #2 · Predicted round-window-membrane permeability of v5.2__aq3__adamantyl__CONHOH__-Cl
Goal. Quantify whether the lead pharmacochaperone candidate can plausibly cross the round-window membrane (RWM) as a topical ear-drop, using Salt & Ma 2001 TMPA baseline as anchor.
Method.
- Stokes-Einstein MW scaling: P ∝ MW^(−1/3) (sphere) from TMPA reference (P = 1.9×10⁻⁸ cm/s, MW 166 Da).
- Lipophilicity correction: empirical Avdeef-style log_factor = 0.5·ΔlogP − 0.0125·ΔTPSA vs TMPA (logP −1.92, TPSA 0).
- Henderson-Hasselbalch f_neutral (CONHOH pKa ≈ 9.0).
- Anchor predicted ST distribution to Salt & Ma 2001 empirical 90-min profile (turn 1 16.5%, turn 2 0.8%).
Script: rwm_permeability.py. Run time <1 s.
Inputs (lead candidate)
| Property | Value | Source |
|---|---|---|
| MW | 371.9 Da | Phase 8d v5.2 library CSV |
| logP | 1.94 | Phase 8d (RDKit Crippen) |
| TPSA | 73.7 Ų | Phase 8d |
| HBD / HBA | 3 / 4 | Phase 8d |
| Rotatable bonds | 1 | Phase 8d |
| pKa (CONHOH) | 9.0 (est.) | hydroxamic-acid literature range 8.5–9.5 (cf. SAHA 9.2) |
Outputs
| Quantity | Value |
|---|---|
| P_TMPA (reference, Salt 2001) | 1.9×10⁻⁸ cm/s |
| P_SE (MW scaled) | 1.45×10⁻⁸ cm/s (factor 0.76 from MW) |
| Lipophilicity factor | ×10.2 (logP/TPSA correction) |
| P_lead (neutral) | 1.48×10⁻⁷ cm/s |
| f_neutral @ pH 7.4 | 0.975 |
| P_lead (effective) | 1.45×10⁻⁷ cm/s |
| Relative to TMPA | 7.6× faster |
Inferred 90-min RWM delivery (anchored to Salt 2001 TMPA distribution)
| Cochlear region | TMPA (Salt 2001) | Lead (predicted) |
|---|---|---|
| Basal turn 1 | 16.5% applied conc | ≈ 100% (saturated) |
| Turn 2 | 0.8% applied conc | ≈ 6% applied conc |
| Basal-turn average | ~8% applied conc | ≈ 60% applied conc |
Sensitivity to pKa
If CONHOH pKa is 8.5 (lower bound of literature range) instead of 9.0:
- f_neutral drops 0.975 → 0.926 (modest)
- P_eff = 1.37×10⁻⁷ cm/s, ratio 7.2× TMPA
- basal avg ≈ 58% — essentially unchanged
The hydroxamic acid stays mostly neutral at perilymph pH; ionization is not the dominant kinetic obstacle.
Interpretation
- The high logP (1.94) more than compensates the ~24% Stokes-Einstein MW penalty: net P is ~7–8× TMPA.
- Predicted basal-turn perilymph concentration after 90-min topical application reaches ~60% of the applied drop concentration.
- For a 100 µM applied drop, that is ~60 µM in the basal turn — comfortably above the µM-Kd target inferred from Phase 5k APBS + Phase 5b dock combined ΔG (−8.19 kcal/mol → Kd ≈ 1 µM in ideal regime).
- The lead is plausibly deliverable as a topical RWM ear-drop under Salt 2001 kinetics.
Caveats
- Avdeef-style lipophilicity factor is empirical. It is not directly quoted in Salt 2001 or 2018; it is the Avdeef 2003 Absorption and Drug Development RWM-correlation rule. Strength of the correction (×10.2) is the dominant uncertainty in the absolute number, but a 3-fold lower factor would still give ~2.5× TMPA — still topically viable.
- No active transport considered. CONHOH is non-substrate for cochlear drug transporters as far as we know; passive diffusion only.
- Inflammation / damaged RWM not modeled. Salt 2018 notes inflammation increases P 2–10×, which would only help.
Connections
[part-of]STRC h01 Phase 8 v5 Library Coulomb-Aware Design 2026-04-24[supports]Delivery claim “topical ear-drop” in[[STRC Pharmacochaperone Virtual Screen E1659A]][ref]2001-salt-ma-quantification-rwm-permeability — TMPA baseline + RWM area + ST clearance[ref]2018-salt-plontke-pharmacokinetic-principles-inner-ear — lipophilicity/TPSA drivers[ref]Avdeef A. 2003 Absorption and Drug Development — empirical logP/TPSA correlation (book, RAG-indexed)