openconf 0.0.9

Conformer generation for drug-like molecules

openconf

a conformer generator for drug-like molecules: uses torsional Monte Carlo moves to quickly generate diverse ensembles, uses RDKit/MMFF94s throughout, and runs fast enough for large-scale workflows.

Installation

pip install openconf

Quick Start

Python API

from rdkit import Chem
from openconf import generate_conformers, ConformerConfig

# From SMILES
mol = Chem.MolFromSmiles("CCCCc1ccccc1")
ensemble = generate_conformers(mol)

print(f"Generated {ensemble.n_conformers} conformers")
print(ensemble.summary())

# Save to SDF
ensemble.to_sdf("output.sdf")

# Or XYZ
ensemble.to_xyz("output.xyz")

Named Presets

Five use-case presets are available out of the box:

from openconf import generate_conformers

ensemble = generate_conformers(mol, preset="rapid")         # fast virtual screening
ensemble = generate_conformers(mol, preset="ensemble")      # property prediction
ensemble = generate_conformers(mol, preset="spectroscopic") # NMR / IR / VCD
ensemble = generate_conformers(mol, preset="docking")       # docking pose recovery

For FEP-style analogue generation from a fixed pose, see generate_conformers_from_pose below.

Custom Configuration

For full control, pass a ConformerConfig directly. You can also use preset_config() as a starting point and override individual fields:

from openconf import generate_conformers, preset_config, ConformerConfig

# Start from a preset and tweak
config = preset_config("docking")
config.max_out = 500
config.random_seed = 42
ensemble = generate_conformers(mol, config=config)

# Or build from scratch
config = ConformerConfig(
    max_out=200,              # Maximum conformers to return
    pool_max=2000,            # Internal pool size
    n_steps=500,              # Exploration steps
    energy_window_kcal=12.0,  # Energy window for filtering
    random_seed=42,           # For reproducibility
)
ensemble = generate_conformers(mol, config=config)

Use-Case Examples

The right configuration depends on the downstream task. Four named presets cover the most common workflows:

from openconf import generate_conformers, preset_config

# One-liner with a preset
ensemble = generate_conformers(mol, preset="docking")

# Or get the config object to inspect / tweak before use
config = preset_config("spectroscopic")
config.max_out = 200          # override a single field
ensemble = generate_conformers(mol, config=config)

Available presets: "rapid", "ensemble", "spectroscopic", "docking", "analogue".

Below are representative wall-clock timings measured on a single CPU core (Apple M2 Pro), mean over 3 runs.

---

1. Rapid — fast virtual screening

Enumerate a handful of diverse shapes per molecule as fast as possible. Appropriate for ligand-based virtual screening at large scale.

• max_out=5, n_steps=30 — minimal per-molecule budget
• do_final_refine=False — skip the final MMFF pass (shape tools re-minimize anyway)
• seed_n_per_rotor=2, seed_prune_rms_thresh=1.5 — coarser seeding
• minimize_batch_size=16 — larger parallel batches for multi-core machines

from openconf import generate_conformers

ensemble = generate_conformers("CC(C)Cc1ccc(cc1)C(C)C(=O)O", preset="rapid")

Full config equivalent

from openconf import ConformerConfig, generate_conformers

config = ConformerConfig(
    max_out=5,
    pool_max=100,
    n_steps=30,
    energy_window_kcal=20.0,
    seed_n_per_rotor=2,
    seed_prune_rms_thresh=1.5,
    do_final_refine=False,
    minimize_batch_size=16,
    dedupe_period=15,
    shake_period=10,
    final_select="diverse",
)
ensemble = generate_conformers("CC(C)Cc1ccc(cc1)C(C)C(=O)O", config=config)

Molecule	Heavy atoms	Rotors	Time (s)	Conformers
butylbenzene	13	3	0.043	5
ibuprofen	18	5	0.046	5
celecoxib	26	4	0.063	5
maraviroc	34	7	0.848	5

At ~45 ms per drug-like molecule on a single core, a 32-core machine processes roughly 60 M molecules/day — sufficient for 1B-scale campaigns with a cluster.

---

2. Ensemble — property prediction

A compact, diverse ensemble for downstream ML or physics-based properties (logP, pKa, conformational descriptors).

• max_out=50, n_steps=200 — balanced quality/speed
• energy_window_kcal=10.0 — includes the thermally accessible range
• final_select="diverse" — maximize chemical diversity over the ensemble

from openconf import generate_conformers

ensemble = generate_conformers("CC(C)Cc1ccc(cc1)C(C)C(=O)O", preset="ensemble")

Full config equivalent

from openconf import ConformerConfig, generate_conformers

config = ConformerConfig(
    max_out=50,
    pool_max=500,
    n_steps=200,
    energy_window_kcal=10.0,
    seed_n_per_rotor=3,
    seed_prune_rms_thresh=1.0,
    do_final_refine=True,
    minimize_batch_size=8,
    final_select="diverse",
)
ensemble = generate_conformers("CC(C)Cc1ccc(cc1)C(C)C(=O)O", config=config)

Molecule	Heavy atoms	Rotors	Time (s)	Conformers
butylbenzene	13	3	0.122	50
ibuprofen	18	5	0.186	50
celecoxib	26	4	0.275	50
maraviroc	34	7	1.580	50

---

3. Spectroscopic — NMR, IR, VCD

Exhaustively populate all thermally accessible conformers with accurate relative MMFF energies for Boltzmann-weighted spectral averaging.

• energy_window_kcal=5.0 — ~3 kcal covers >99% of the Boltzmann population at 300 K; 5 kcal provides margin for MMFF error
• final_select="energy" — return lowest-energy conformers; weight by exp(-E/kT)
• parent_strategy="softmax" — bias sampling toward low-energy basins
• seed_n_per_rotor=5, seed_prune_rms_thresh=0.5 — dense seeding to avoid missing shallow minima
• do_final_refine=True — accurate relative energies are critical here

from openconf import generate_conformers

ensemble = generate_conformers("CC(C)Cc1ccc(cc1)C(C)C(=O)O", preset="spectroscopic")

# Boltzmann weights at 298.15 K (override via ``temperature``, in Kelvin)
weights = ensemble.boltzmann_weights()

Full config equivalent

from openconf import ConformerConfig, generate_conformers

config = ConformerConfig(
    max_out=100,
    pool_max=1000,
    n_steps=400,
    energy_window_kcal=5.0,
    seed_n_per_rotor=5,
    seed_prune_rms_thresh=0.5,
    do_final_refine=True,
    minimize_batch_size=8,
    parent_strategy="softmax",
    final_select="energy",
)
ensemble = generate_conformers("CC(C)Cc1ccc(cc1)C(C)C(=O)O", config=config)

Molecule	Heavy atoms	Rotors	Time (s)	Conformers
butylbenzene	13	3	0.181	91
ibuprofen	18	5	0.327	100
celecoxib	26	4	0.289	36
maraviroc	34	7	2.374	75

Fewer conformers for celecoxib/maraviroc reflect the tight 5 kcal window — rigid, aromatic-rich scaffolds have few populated conformers at room temperature.

---

4. Docking Pose Recovery

Maximize the chance that the bioactive conformation is in the output set, i.e. minimize best-RMSD-to-crystal across the ensemble. This is the right choice when preparing a single compound for docking where conformer quality matters. For bulk library preparation (thousands of molecules), "rapid" is usually more appropriate.

• parent_strategy="uniform" — broad exploration; energy-biased sampling hurts recall of strained bioactive conformers
• energy_window_kcal=18.0 — bioactive conformations are often 5–15 kcal above the MMFF global minimum
• do_final_refine=False — docking programs minimize inside the binding site; pre-minimized geometries can hurt pose recall
• max_out=250, n_steps=500 — larger ensemble improves recall at acceptable cost

from openconf import generate_conformers

ensemble = generate_conformers("CC(C)Cc1ccc(cc1)C(C)C(=O)O", preset="docking")
ensemble.to_sdf("output.sdf")

Full config equivalent

from openconf import ConformerConfig, PrismConfig, generate_conformers

config = ConformerConfig(
    max_out=250,
    pool_max=2500,
    n_steps=500,
    energy_window_kcal=18.0,
    seed_n_per_rotor=4,
    seed_prune_rms_thresh=0.8,
    do_final_refine=False,
    minimize_batch_size=8,
    parent_strategy="uniform",
    final_select="diverse",
    prism_config=PrismConfig(energy_window_kcal=18.0),
)
ensemble = generate_conformers("CC(C)Cc1ccc(cc1)C(C)C(=O)O", config=config)
ensemble.to_sdf("docking_input.sdf")

Molecule	Heavy atoms	Rotors	Time (s)	Conformers
butylbenzene	13	3	0.232	140
ibuprofen	18	5	0.326	169
celecoxib	26	4	0.397	231
maraviroc	34	7	1.826	172

---

5. Analogue / FEP-style R-group exploration

Generate conformers for an MCS-aligned analogue while keeping the core scaffold exactly fixed at the input pose. The correct entry point here is generate_conformers_from_pose rather than generate_conformers.

• Starts from the supplied conformer — no ETKDG seeding
• Only free terminal rotors are explored (those whose moving fragment is entirely outside the constrained core)
• MMFF minimization uses stiff position restraints on all constrained atoms, then snaps them to exact starting coordinates so there is zero drift
• Global shake is suppressed to avoid thrashing the starting pose

from rdkit import Chem
from rdkit.Chem import AllChem
from openconf import generate_conformers_from_pose

# Suppose we have an MCS-aligned analogue with a propyl substituent
# replacing the butyl chain on a benzene scaffold.
mol = Chem.MolFromSmiles("CCCc1ccccc1")
mol = Chem.AddHs(mol)
AllChem.EmbedMolecule(mol, AllChem.ETKDGv3())

# Ring heavy-atom indices — these must not move
ring_atoms = [3, 4, 5, 6, 7, 8]

ensemble = generate_conformers_from_pose(mol, constrained_atoms=ring_atoms)
ensemble.to_sdf("analogues.sdf")

The default preset ("analogue") returns up to 50 conformers. Pass preset= or config= to override:

from openconf import ConformerConfig, generate_conformers_from_pose

# Fewer conformers, faster turnaround
config = ConformerConfig(max_out=10, n_steps=60, pool_max=200)
ensemble = generate_conformers_from_pose(mol, constrained_atoms=ring_atoms, config=config)

Full analogue preset equivalent

from openconf import ConformerConfig, PrismConfig, generate_conformers_from_pose

config = ConformerConfig(
    max_out=50,
    pool_max=500,
    n_steps=150,
    energy_window_kcal=10.0,
    do_final_refine=True,
    minimize_batch_size=8,
    parent_strategy="softmax",
    final_select="diverse",
    prism_config=PrismConfig(energy_window_kcal=10.0),
)
ensemble = generate_conformers_from_pose(mol, constrained_atoms=ring_atoms, config=config)

---

Configuration Quick Reference

Parameter	Rapid	Ensemble	Spectroscopic	Docking	Analogue
max_out	5	50	100	250	50
n_steps	30	200	400	500	150
energy_window_kcal	20	10	5	18	10
seed_n_per_rotor	2	3	5	4	—
seed_prune_rms_thresh	1.5	1.0	0.5	0.8	—
do_final_refine	False	True	True	False	True
parent_strategy	softmax	softmax	softmax	uniform	softmax
final_select	diverse	diverse	energy	diverse	diverse

Analogue mode uses generate_conformers_from_pose; seeding parameters are unused because ETKDG is skipped.

How It Works

1. Seeding

Generates initial conformers using RDKit's ETKDGv3 algorithm. The seed count is computed automatically from molecular topology. For molecules with small non-aromatic rings, ETKDGv3's useSmallRingTorsions is enabled; for macrocycles (rings ≥ 10 atoms), useMacrocycleTorsions is enabled, applying crystallography-derived distance bounds for better ring-closure geometries.

When n_seeds=None, openconf resolves a seed plan before embedding. Explicit n_seeds values are always honored. Macrocycles keep dense topology-derived seed budgets for ring-pucker discovery, while simple low-flexibility acyclic molecules and large flexible hydrocarbons use data-backed reduced budgets to avoid redundant RDKit embeddings.

2. Hybrid Exploration

The default "hybrid" strategy combines:

• Torsion library: 365 crystallography-derived SMARTS rules (RDKit CrystalFF, Riniker & Landrum 2016) with Boltzmann-weighted angle preferences
• MCMM moves: random torsion perturbations biased by the library
• Correlated moves: simultaneous changes to adjacent rotors
• Ring flip moves: SVD plane-reflection of non-aromatic 5–7-membered rings to sample chair/envelope inversions
• Global shakes: periodic large perturbations to escape local basins

3. Minimization

Each proposed conformer is minimized with MMFF94s to ensure physically reasonable geometries.

4. Deduplication

Uses PRISM Pruner for efficient duplicate removal via moment-of-inertia filtering followed by RMSD-based pruning.

5. Selection

Final selection returns the lowest-energy conformers after PRISM deduplication.

For the full algorithm description and parameter tuning guide, see SCIENCE.md.

Benchmarks

Validated on the Iridium benchmark (120 drug-like molecules, bioactive conformer recovery from crystal structures). At N=200, openconf achieves a median best-RMSD of 0.58 Å vs. 0.63 Å for ETKDG+MMFF94s, at 10–15× lower wall time. The advantage is concentrated in flexible molecules (7–9 rotatable bonds), where openconf's torsion-library biasing and ring flip moves outperform pure distance-geometry seeding.

openconf is not recommended for macrocycles (ring size ≥ 12). On macrocyclic ring systems, ETKDG+MMFF94s with a large conformer budget outperforms openconf in both RMSD and ensemble coverage metrics. ETKDGv3 has dedicated macrocycle distance-geometry bounds that openconf does not replicate.

API Reference

Main Functions

• generate_conformers(mol, method="hybrid", config=None) - Main entry point
• generate_conformers_from_smiles(smiles, ...) - Convenience wrapper
• generate_conformers_from_pose(mol, constrained_atoms, config=None) - FEP-style analogue generation from an aligned pose

Configuration Classes

• ConformerConfig - Main configuration
• PrismConfig - PRISM Pruner settings
• ConstraintSpec - Positional constraints for pose-locked generation

Data Classes

• ConformerEnsemble - Container for conformers and metadata
• ConformerRecord - Per-conformer metadata

Lower-Level Components

• prepare_molecule(mol) - Sanitize and add hydrogens
• build_rotor_model(mol) - Identify rotatable bonds and flippable rings
• TorsionLibrary - 365 crystallography-derived SMARTS torsion rules; load custom rules with TorsionLibrary.from_json(path)
• prism_dedupe(mol, conf_ids, config) - Deduplication

Dependencies

• RDKit >= 2022.03
• NumPy >= 1.20
• prism-pruner >= 0.0.3

License

MIT License

Citation

If you use openconf in your research, please cite:

@software{openconf,
  title = {openconf: Modular conformer generation for docking and ensemble workflows},
  year = {2026},
  url = {https://github.com/rowansci/openconf}
}

Acknowledgments

• PRISM Pruner by Nicolò Tampellini for efficient conformer deduplication
• RDKit for cheminformatics infrastructure and the CrystalFF torsion library (Riniker & Landrum, J. Chem. Inf. Model. 56, 2016)