What are the druggable allosteric sites on neuronal protein interaction hub proteins?

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Composite

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Novelty

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Mechanistic

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Druggability

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Priority

85%

Importance

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Tractability

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Market price

50%

Description

The medicinal chemist noted that PPI interfaces are typically undruggable, requiring identification of cryptic allosteric binding sites. This structural knowledge gap prevents rational design of small molecule interaction stabilizers for neurological diseases.

Source: Debate session sess_SDA-2026-04-08-gap-pubmed-20260406-062222-cc3bcb47 (Analysis: SDA-2026-04-08-gap-pubmed-20260406-062222-cc3bcb47)

Resolution criteria

Resolution requires: (1) cryo-EM or NMR structural determination of >=3 neuronal protein interaction hub complexes (p53-MDM2, beta-catenin-APC, Kalirin-PDZ) identifying cryptic allosteric sites with pocket volume >=150 A^3; (2) fragment-based screening or molecular dynamics (>=1 mus) identifying small molecule hits (MW <500) that bind allosteric sites with KD <=10 uM; (3) cellular validation of allosteric modulators showing functional consequence (>=30% modulation of PPI activity) without disrupting normal protein folding or essential interactions. Computational pocket identification without experimental validation of druggability is insufficient.

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