Boltz Small Molecule Design

Workflow

If boltz-api is missing from PATH, use boltz-cli-setup for install/update guidance before retrying. If a command reports missing or expired authentication, use boltz-cli-setup to start boltz-api auth login --device-code before retrying; do not ask permission first. If the agent host sandbox blocks boltz-api install/auth/API calls, use boltz-cli-setup to request the host sandbox bypass/escalation needed for user-wide CLI install, browser login, credential storage, temp files, or API access before retrying.

Use this skill when the user wants de novo small-molecule binders (no existing library).

1. Normalize the target: one or more protein sequences into target.entities, plus optional pocket_residues (0-based) and/or reference_ligands (known binders to help locate the pocket).
2. Pick num_molecules — valid range 10 to 1,000,000 (server rejects outside it). If the user says fewer than 10, explain the floor and propose 10.
3. Only add chemical_space (e.g. "enamine_real") if the user explicitly wants generation restricted to synthesizable molecules within that library.
4. Supported optional features include chemical_space and molecule_filters; only add them on explicit request. Read references/api.md [blocked] for exact shapes and filter options.
5. Author the payload YAML or JSON, run estimate-cost, show the USD cost, wait for explicit confirmation. Cost is a flat $0.025 per molecule (size-independent); still quote estimated_cost_usd from the response as the authoritative total.
6. start to submit (synchronous). Capture the ID.
7. Launch download-results through the runtime's long-running or non-blocking command facility; it polls, paginates, downloads per-hit structures, and exits when terminal. Use the mechanism the runtime documents; consult boltz-cli-setup if unsure. After launching the downloader, always report the job ID, run name, and output directory. If the runtime can schedule follow-up checks, schedule a download-status check and state the cadence; otherwise include the download-status command.
8. Rank hits from <output-root>/<run-name>/results/index.jsonl by binding_confidence for hit discovery or optimization_score for lead optimization. Each generated molecule also carries a free adme block (solubility, permeability, lipophilicity) — surface it for developability triage when the user cares about ADME, or when a top hit looks risky. Read references/results.md [blocked] for output layout and metric details.

Command Pattern

# Replace placeholders with concrete absolute paths before running.# Use a short descriptive run name, for example: sm-design-<target>-<batch>-v1
boltz-api small-molecule:design estimate-cost \  --input @yaml:///absolute/path/payload.yaml
boltz-api small-molecule:design start \       --idempotency-key "<run-name>" \       --input @yaml:///absolute/path/payload.yaml \       --raw-output --transform id
# Copy the printed job ID into this command, then launch it through the# runtime's long-running/non-blocking command facility (consult boltz-cli-setup# if unsure). Do not detach it with shell "&" or nohup unless the runtime# documents shell backgrounding as its supported mode.boltz-api download-results \  --id "<job-id-from-start>" --name "<run-name>" \  --root-dir "/absolute/path/boltz-experiments" \  --poll-interval-seconds 60# -> /absolute/path/boltz-experiments/<run-name>/results/<pres_*>/...

Payload keys are num_molecules, target, chemical_space, molecule_filters — the API body field names.

Always Do This

• Enforce 10 <= num_molecules <= 1,000,000 before calling estimate-cost. The server rejects values outside that range.
• Cost is a flat $0.025 per molecule (size-independent). estimate-cost returns the authoritative total.
• Treat pocket residue indices as 0-based.
• Keep payload field names exactly as the API body names shown in references/api.md.
• Use absolute paths for the output root, payload files, and embedded target files. Do not cd into the run directory for follow-up commands; pass the same --root-dir and use absolute paths so later relative paths do not drift.
• Prefer one merged top-level payload via --input @yaml:///absolute/path/payload.yaml or @json:///absolute/path/payload.json for estimate-cost and start. Keep --idempotency-key and --workspace-id top-level; if they also appear inside --input, the top-level flags win.
• Direct object flags still work as overrides: for example --target @yaml:///absolute/path/target.yaml or --molecule-filters @json:///absolute/path/filters.json. Piped YAML / JSON on stdin also works, but it must use API body field names. Never use @file://.
• Use the same slug as both --idempotency-key at submit and --name on download-results.
• In permission-gated runtimes, keep each Boltz call as a top-level command that starts with boltz-api. Prefer concrete arguments over sh -c, inline environment assignments, aliases, wrapper scripts, loops, or pipelines around the boltz-api invocation unless the user already allowed that exact command form. Use --raw-output --transform id, read the printed ID, then paste that literal ID into the next download-results command.
• Run download-results through the runtime's long-running or non-blocking command facility, using the mechanism the runtime documents rather than tool arguments you assume exist. Do not detach it with shell & or nohup unless the runtime documents shell backgrounding as its supported mode; some tool runners reap shell-backgrounded children before .boltz-run.json is written. If unsure how this runtime handles long-running commands, consult boltz-cli-setup.
• After the download starts, do not manually wait on it or run ad hoc polling loops. Wall-clock time scales roughly with num_molecules: under 100 often finishes in a few minutes, 100-1,000 may take several minutes to tens of minutes, and larger runs can take longer or hours depending on inputs and system load. Don't quote a fixed duration. --poll-interval-seconds 60 is a sensible default for the downloader. download-results emits JSONL progress on stderr by default; add --progress-format text --verbose only when you explicitly want human-readable logs.
• If the runtime can schedule follow-up checks (a heartbeat, scheduled task, or reminder), schedule one after launching download-results. It should run boltz-api --format json download-status --name "<run-name>" --root-dir "/absolute/path/boltz-experiments", post only material status changes or terminal completion/failure, and stop once terminal. Choose cadence by num_molecules: under 100 -> every 1-2 minutes; 100-1,000 -> every 5 minutes; over 1,000 -> every 15 minutes. If the runtime cannot schedule follow-ups, do not claim an automatic next check: report the job ID, run name, output directory, and the download-status command. Poll a saved session handle only for interactive, user-requested progress checks; never run a manual poll loop in the current turn.
• If detached download needs to be restarted, re-run boltz-api download-results with the same --name "<run-name>" and the same --root-dir.
• Do not invent filters; only add molecule_filters on user request.

Escape Hatch

• Payload reference: https://api.boltz.bio/docs/api/python/resources/small_molecule/subresources/design/methods/start
• CLI flag names: boltz-api small-molecule:design start --help

Read references/api.md [blocked] for the target, chemical_space, and molecule_filters shapes (filter catalog matches the screen endpoint). Read references/results.md [blocked] after download when ranking generated molecules or explaining outputs.

Outputs

Rank from results/index.jsonl after download-results; use references/results.md [blocked] for local file layout and metric meanings.