| name | boltz-small-molecule-design |
| description | Design new small-molecule binders with Boltz. Use when generating novel ligands or hits for a target without a fixed compound library. Not for screening existing molecules or one-off docking. |
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).
- 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).
- 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.
- Only add
chemical_space (e.g. "enamine_real") if the user explicitly wants generation restricted to synthesizable molecules within that library.
- 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.
- 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.
start to submit (synchronous). Capture the ID.- 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.
- 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
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
boltz-api download-results \
--id "<job-id-from-start>" --name "<run-name>" \
--root-dir "/absolute/path/boltz-experiments" \
--poll-interval-seconds 60
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.
Escape Hatch
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.
