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 seed pocket detection).
2. Pick num_molecules — minimum 10, server rejects anything lower. If the user says a smaller number, explain the floor and propose 10.
3. Only add chemical_space (e.g. "enamine_real") if the user explicitly wants synthesis-aware generation 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 approximately $0.025 per molecule for small targets (may scale with complex size); always quote estimated_cost_usd from the response rather than a hardcoded formula.
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 later polling. After launching it, report the job ID, run name, and output directory, then end the turn immediately. Do not wait on the background session unless the user explicitly asks for progress.
8. Rank hits from <output-root>/<run-name>/results/index.jsonl by binding_confidence for hit discovery or optimization_score for lead optimization. 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 num_molecules >= 10 before calling estimate-cost. The server rejects smaller batches.
• Cost is approximately $0.025 per molecule for small targets (may scale with complex size). Always quote estimated_cost_usd from estimate-cost rather than a hardcoded per-molecule rate.
• 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 wait on it or poll it. Design jobs can run 30 min to a few hours — --poll-interval-seconds 60 is a sensible default. download-results emits JSONL progress on stderr by default; add --progress-format text --verbose only when you explicitly want human-readable logs. Report the job ID, run name, output directory, and that the runtime should notify when the background command completes.
• Only check status when the user asks. In Codex, poll the saved session with an empty write_stdin, or prefer boltz-api --format json download-status --name "<run-name>" --root-dir "/absolute/path/boltz-experiments" for structured local checkpoint state. Never run a manual poll loop.
• 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.