feat(danuglipron): the substitution golden path, end to end on 7LCJ - #102
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Included review availability: Your plan provides up to 10 included reviews per hour; 6 remain after this review. 📝 WalkthroughWalkthroughThe PR adds a command-line danuglipron substitution scan with seeded embedding, descriptor reporting, pocket-charge prescreening, and matched-site dependence statistics. Regression tests cover matched-site spread and unmeasurable cases. ChangesSubstitution scan
Priority: ⬇️ Low Estimated code review effort: 3 (Moderate) | ~25 minutes Change: Feature Sequence Diagram(s)sequenceDiagram
participant CLI
participant main
participant RDKit
participant Prescreen
CLI->>main: Parse scan options
main->>RDKit: Enumerate and embed substitutions
main->>Prescreen: Score embedded poses
Prescreen->>RDKit: Compute ligand charges
Prescreen-->>main: Return scored rows
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In `@experiments/danuglipron/run_substitution_scan.py`:
- Line 195: Update the proposal data flow to retain a stable parent-site
identifier alongside each substituent score, then compute between from scores of
different substituents matched to the same parent site rather than from allv
across every site. Preserve the existing per-site rows and output while ensuring
the reported ratio represents substituent-identity variation only.
- Line 162: Update the coordinate transformation in embed_proposals so each
generated conformer is centered by subtracting the centroid of e.coords before
applying the pocket translation (cx, cy, cz). Preserve the existing
moved-coordinate structure while ensuring the resulting ligand centroid aligns
with the pocket centroid.
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experiments/danuglipron/run_substitution_scan.pytools/pipeline/substitution.pytools/pipeline/tests/test_substitution.py
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CodeRabbit, PR #102. `_prescreen` added the pocket centroid straight to `e.coords`, which is whatever ETKDG produced. ETKDG does not promise an origin-centred conformer. MEASURED over embeddings from this script's own path (AddHs + ETKDG, seed 0xF00D), |centroid| in Angstrom: CC(C)c1ccccc1O 0.0000 c1ccccc1 0.0000 CN1CCN(CC1)c1ccccc1 0.0000 CC(=O)Nc1ccc(O)cc1 0.1807 CCCCCCCC 0.2452 So the displacement is real but not uniform -- it is zero for some analogues and ~0.2 A for others, which is worse than a constant offset: it perturbs the BETWEEN-substituent comparison this scan exists to make, which is the one quantity the output is read for, and does so silently. Fixed in `_prescreen` rather than in `embed_proposals`, because `embed_proposals` documents itself as the general geometry hop and has other callers; placing a ligand in a pocket is the claim THIS function makes, so it is where the centring belongs. ruff format + ruff check clean. Co-Authored-By: Claude Opus 5 (1M context) <noreply@anthropic.com>
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Addressed in
MEASURED over embeddings from this script's own path ( So it is real but not uniform — which is worse than a constant offset would be. A constant shift moves every pose the same way and largely cancels in a ranking; this is zero for some analogues and ~0.2 Å for others, so it perturbs exactly the between-substituent comparison the scan exists to make, and does it silently. Fixed in |
Everything in this pipeline had been demonstrated only in throwaway scripts.
This commits it as a runnable experiment against the real parent (PubChem CID
134611040) and the real receptor (7LCJ), so the result survives the session
that produced it.
S1 enumerate substituent_scan, per SITE
S2 descriptors RELATIVE to the parent
S3 embed seeded ETKDG -> 3-D
S4 pocket pdb2pqr -> 6458 point charges, derived ONCE
S5 prescreen classical field at the ligand's atoms, no SCF
MEASURED, full run: 54 analogues from 6 substituents, 55/55 embedded, 0 failed.
## The finding that determines the pipeline's unit of work
BETWEEN substituents : 68.16 kcal/mol
WITHIN one substituent: 63.94 kcal/mol (same group, different ring site)
ratio : 0.94
**Where you put the group matters as much as which group it is.** A pipeline
reporting one number per SUBSTITUENT -- which is what a descriptor gate does,
and what funnel.py is shaped for (one row per iso.canonical) -- averages over a
variable as large as the one it is trying to measure.
This REPRODUCES INDEPENDENTLY: an earlier 4-substituent probe on benzoic acid
gave 0.95 on a different molecule with a different substituent count. Two
constructions, same conclusion.
So this script reports per (substituent, SITE) and never aggregates to a
per-label mean. The one place it DOES aggregate -- the dMW/dcLogP/dTPSA table
-- is annotated as safe precisely because those three are site-independent by
construction, and nothing downstream of the pocket is.
## Two negative results it also demonstrates
Absolute descriptor gates are useless on a real lead: danuglipron is MW 555.6,
cLogP 4.89 -- a Phase-2 clinical compound that already violates Lipinski, so an
absolute rule-of-5 gate rejects 54/54 and ranks nothing. The rule of 5 is a
hit-finding filter; on an optimized molecule it is a constant.
The pharmacophore gate cannot reject a substituent scan -- swapping an aromatic
CH cannot break an acid, a fused diazole, a basic amine or a nitrile (54/54
kept). Verified REACHABLE separately, so that is a true negative rather than an
inert gate: a methyl ester breaks it, benzene and ethanol break all four
features, the parent passes. It belongs on SCAFFOLD moves.
## Scope, stated because a ranked table invites over-reading
No docking, no xtb, no QM. The prescreen is a classical Coulomb score against a
FIXED pose translated to the pocket centroid, so it measures the METHOD's
response to placement, not a binding affinity. A production run docks each
analogue first. Remaining blockers -- pose noise (per-pose sd 29.07 kcal/mol
against 1-2 kcal/mol substituent effects) and QM/MM dispersion -- are in
wiki/substitution-pipeline-danuglipron-2026-09-19.md.
Stacked on #96 (feat/substitution-pipeline), which provides
`propose_substitutions` and `embed_proposals`.
Co-Authored-By: Claude Opus 5 (1M context) <noreply@anthropic.com>
CodeRabbit, PR #102. `_prescreen` added the pocket centroid straight to `e.coords`, which is whatever ETKDG produced. ETKDG does not promise an origin-centred conformer. MEASURED over embeddings from this script's own path (AddHs + ETKDG, seed 0xF00D), |centroid| in Angstrom: CC(C)c1ccccc1O 0.0000 c1ccccc1 0.0000 CN1CCN(CC1)c1ccccc1 0.0000 CC(=O)Nc1ccc(O)cc1 0.1807 CCCCCCCC 0.2452 So the displacement is real but not uniform -- it is zero for some analogues and ~0.2 A for others, which is worse than a constant offset: it perturbs the BETWEEN-substituent comparison this scan exists to make, which is the one quantity the output is read for, and does so silently. Fixed in `_prescreen` rather than in `embed_proposals`, because `embed_proposals` documents itself as the general geometry hop and has other callers; placing a ligand in a pocket is the claim THIS function makes, so it is where the centring belongs. ruff format + ruff check clean. Co-Authored-By: Claude Opus 5 (1M context) <noreply@anthropic.com>
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…e within `_report_site_dependence` answers the question that sets this pipeline's unit of work: does WHERE a group goes matter as much as WHICH group it is? Per-substituent mean, or the (substituent, site) pair? It computed "BETWEEN substituents" as the range over EVERY (substituent, site) score. That pool already CONTAINS the within-substituent site variation, so the printed ratio compared a subset against its own superset. Two consequences: 1. the ratio is bounded by 1 BY CONSTRUCTION -- it can never report that site matters MORE than identity, however strongly the data say so; 2. it cannot distinguish "site matters as much as identity" from "site is most of what the pooled range measures", which are opposite conclusions with opposite consequences for the pipeline's design. Now computed at MATCHED SITES: at each site index, the spread across DIFFERENT substituents. That holds placement fixed and isolates identity, which is the comparison the printed line claims to be making. When no site index carries more than one substituent the two axes are perfectly confounded, and it now SAYS SO instead of computing anything. Falling back to the pooled range there would silently reinstate the bug in exactly the case where it misleads most. tests/test_site_dependence_statistic.py is built around inputs where the two formulas DISAGREE -- an input where they happen to agree would pass either way and prove nothing. The discriminating assertion is that the ratio CAN EXCEED 1 (measured 200.0 on a constructed case); the pooled formula caps it at 1 always, so a ratio above 1 is proof of which comparison ran rather than an incidental value. MUTATION-TESTED: reverting to the pooled range fails 2 of 4; making the confounded case fall back to the pool fails 1. Both killed. Reported by CodeRabbit on #102. Co-Authored-By: Claude Opus 5 (1M context) <noreply@anthropic.com>
mgoldey
added a commit
that referenced
this pull request
Sep 19, 2026
CodeRabbit, PR #102. `_prescreen` added the pocket centroid straight to `e.coords`, which is whatever ETKDG produced. ETKDG does not promise an origin-centred conformer. MEASURED over embeddings from this script's own path (AddHs + ETKDG, seed 0xF00D), |centroid| in Angstrom: CC(C)c1ccccc1O 0.0000 c1ccccc1 0.0000 CN1CCN(CC1)c1ccccc1 0.0000 CC(=O)Nc1ccc(O)cc1 0.1807 CCCCCCCC 0.2452 So the displacement is real but not uniform -- it is zero for some analogues and ~0.2 A for others, which is worse than a constant offset: it perturbs the BETWEEN-substituent comparison this scan exists to make, which is the one quantity the output is read for, and does so silently. Fixed in `_prescreen` rather than in `embed_proposals`, because `embed_proposals` documents itself as the general geometry hop and has other callers; placing a ligand in a pocket is the claim THIS function makes, so it is where the centring belongs. ruff format + ruff check clean. Co-Authored-By: Claude Opus 5 (1M context) <noreply@anthropic.com>
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Stacked on #96 — retarget to
mainonce that merges.Everything in this pipeline had been demonstrated only in throwaway
/tmpscripts. This commits it as a runnable experiment against the real parent (PubChem CID 134611040) and the real receptor (7LCJ), so the result outlives the session that produced it.Measured, full run: 54 analogues from 6 substituents, 55/55 embedded, 0 failed.
The finding that determines the pipeline's unit of work
Where you put the group matters as much as which group it is.
A pipeline reporting one number per substituent — which is what a descriptor gate does, and what
funnel.pyis shaped for (one row periso.canonical) — averages over a variable as large as the one it's measuring.This reproduces independently: an earlier 4-substituent probe on benzoic acid gave 0.95 — different molecule, different substituent count, same conclusion. Two constructions agreeing is the part worth trusting.
So the script reports per (substituent, site) and never aggregates to a per-label mean. The one place it does aggregate — the ΔMW/ΔcLogP/ΔTPSA table — is annotated as safe precisely because those three are site-independent by construction, and nothing downstream of the pocket is.
Two negative results it also demonstrates
Absolute descriptor gates are useless on a real lead. Danuglipron is MW 555.6, cLogP 4.89 — a Phase-2 compound that already violates Lipinski, so an absolute rule-of-5 gate rejects 54/54 and ranks nothing.
The pharmacophore gate cannot reject a substituent scan — swapping an aromatic CH can't break an acid, a fused diazole, a basic amine or a nitrile (54/54 kept). Verified reachable separately, so it's a true negative rather than an inert gate: a methyl ester breaks it, benzene and ethanol break all four, the parent passes. It belongs on scaffold moves.
Scope, because a ranked table invites over-reading
No docking, no xtb, no QM. The prescreen is a classical Coulomb score against a fixed pose translated to the pocket centroid, so it measures the method's response to placement, not a binding affinity. A production run docks each analogue first.
Remaining blockers — pose noise (per-pose sd 29.07 kcal/mol against 1–2 kcal/mol substituent effects) and QM/MM dispersion — are documented in the wiki note.
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