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 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 with the agent runtime's background/non-blocking command facility; it polls, paginates, downloads per-hit structures, and exits when terminal. In Claude Code, use Bash with run_in_background: true. In Codex, run download-results as a foreground shell command with yield_time_ms: 1000; if Codex returns a session_id, keep it for optional same-thread polling, but treat download-status plus the run directory as the durable source of truth. In Codex app/desktop runtimes that expose same-thread heartbeat automations, create a heartbeat that checks download-status periodically and posts a concise completion or failure update when the download reaches a terminal state. After launching the downloader, always report the job ID, run name, and output directory. Include the next check cadence if the heartbeat was created; 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 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 in the agent
# runtime's background/non-blocking mode.
# Claude Code: Bash with run_in_background=true.
# Codex: foreground shell command with yield_time_ms=1000; keep the returned session_id if one is provided.
# Do not append "&" or use nohup in Codex.
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 agents such as Claude Code, 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.
• Prefer the agent runtime's background/non-blocking command mode for download-results. In Codex specifically, keep download-results in the foreground and set the shell tool yield to 1000 ms; Codex will return a session_id if the command is still running. Do not append & or use nohup in Codex because the tool runner may clean up shell-backgrounded descendants before .boltz-run.json is fully written.
• After the background/session 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.
• In Codex app/desktop runtimes with same-thread heartbeat automation support, schedule a heartbeat after launching download-results. The heartbeat should run boltz-api --format json download-status --name "<run-name>" --root-dir "/absolute/path/boltz-experiments" 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. Post only material status changes or terminal completion/failure. Poll the saved session_id with an empty write_stdin only for interactive, user-requested progress checks. Never run a manual poll loop in the current turn.
• If the current host has no heartbeat automation support, do not claim an automatic next check. Report the job ID, run name, output directory, and the command needed to check download-status.
• 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 for the target, chemical_space, and molecule_filters shapes (filter catalog matches the screen endpoint). Read references/results.md after download when ranking generated molecules or explaining outputs.

Outputs

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