comp-pharm-cascade

comp-pharm-cascade

Orchestration skill: how a target + ligand series flows through the available compute stack to a defensible affinity/mechanism result. This is a routing law over executor skills, not a new engine. Reference implementation: the phenibut α2δ-1 / GABA_B campaign (worked numbers at the bottom).

Core principle — a cascade with two guarded gates

Escalate cost only when the cheaper tier can't answer. But a naive cascade is brittle where campaigns actually break: it trusts each tier and escalates upward, so a wrong pose makes MM-GBSA, FEP, and QM all rank garbage equally. So spend redundancy surgically at the two checkpoints where being wrong is catastrophic and silent, single-track everywhere else.

• Gate 1 — Pose. A pose is trusted only when independent methods agree (Boltz-2 co-fold ipTM/PAE ∩ Glide/IFD ∩ BPMD stability). Cheap ensemble at the known failure point. Never rescore an unvalidated pose.
• Gate 2 — The published number. The one headline ΔΔG gets FEP plus one orthogonal corroborator (Boltz affinity or QM decomposition) plus the experimental value. Everything else in the SAR runs single-method, flagged lower-confidence.

Tier map (cheap → expensive)

Tier	Capability	Executor	Note
0 — Anchor ⭐	Experimental Ki/IC50/EC50, the y-axis	ChEMBL MCP / GtoPdb / tooluniverse pharmacology	Run FIRST. No ground truth → no rankable claim (see Gate 0).

Canonical phase pipeline

Substrate & ops (hard-won)

Worked reference — phenibut (2026-07-04)