Design

From a rare IDP state to a practical shortlist, then back to experiment.

Open silver and graphite intrinsically disordered protein conformations arc across a pale field around one violet transient pocket and sparse schematic molecular fragments.

Rare state to experimental dynamics fingerprint

Design starts with a transient pocket in a rare IDP state.

Modelling identifies a local pocket that appears only in a rare conformation of the disordered ensemble. Multiple AI approaches can then explore sourceable chemistry against that same structural hypothesis before matched HDX-MS tests the resulting candidates.

Scroll to run the sequence 5 stages / 25 frames
Resolve a rare pocket An open intrinsically disordered protein ensemble with one selected rare conformation and a local violet transient pocket.

Resolve a rare pocket

Ensemble modelling identifies a shallow pocket that exists only when distant segments of the disordered chain make a temporary local contact.

Explore with multiple models Several schematic small molecules approach the same transient pocket from different directions around an open IDP ensemble.

Explore with multiple models

Different AI models test complementary small-molecule hypotheses against the same ensemble-aware pocket rather than treating one structure as ground truth.

Constrain to sourceable chemistry A sparse commercial building-block inventory connects selected schematic fragments to the same transient IDP pocket.

Constrain to sourceable chemistry

The search is grounded in commercial vendor libraries so selected building blocks can be accessed on a 3 to 4 week timeline.

Narrow the search A dense neutral molecular field passes through three selection stages and resolves into a sparse row of shortlisted candidates.

Narrow the search

A 12 billion compound search space is filtered to approximately 100 to 300 candidates for experimental prioritisation.

Return to HDX-MS Two matched open IDP conditions compare protein alone with protein plus compound, with a local violet protection difference and deterministic uptake meters.

Return to HDX-MS

Matched protein-alone and compound-treated experiments compare protection and exchange kinetics to evaluate engagement and changes in IDP structural dynamics.

Evidence gate

Experiment decides what advances.

A docking hypothesis earns progression only when matched HDX-MS produces a reproducible protection and kinetics fingerprint.

Docking becomes an evidence decision

Generative design evidence path

A modeled docking hypothesis and matched HDX-MS evidence merge into engagement, dynamics, and designability gates. Convergent evidence advances the candidate, while weak or inconsistent evidence returns the hypothesis to design.

Modeled hypothesis

Pocket-fit proposal

Docking proposes where sourceable chemistry could engage the transient pocket. It does not establish a bound pose.

Modeled

Matched HDX-MS

Protection + kinetics

Protein-alone and compound-treated measurements test local protection and exchange behavior under matched conditions.

Measured

Convergent evidence

Model and experiment agree
  1. 01

    Engagement

    Is local protection reproducible?

    A consistent protected region supports direct engagement with the selected IDP state.

  2. 02

    Dynamics

    Do exchange kinetics change coherently?

    Time-dependent uptake reveals whether the compound changes local ensemble behavior.

  3. 03

    Designability

    Can the chemistry be made and improved?

    Sourceable building blocks and tractable analogues keep the hypothesis inside a practical design cycle.

Evidence decision

Advance

Convergent signal

Reproducible protection, coherent kinetics, and practical chemistry justify the next experimental step.

Return to design

Update the hypothesis

Weak, diffuse, or inconsistent evidence redirects the pocket model, chemistry, or experimental design.

Refine model or chemistry

Evidence directs the next design.

Every measured fingerprint becomes a design instruction, either advancing a candidate or refining the hypothesis for the next cycle.

Next: 04 Validation