bio-shape-similarity

Version Compatibility

Reference examples tested with: RDKit 2024.09+ (Open3DAlign and USRCAT); official ShaEP syntax checked against ShaEP 1.4.2; ROCS/FastROCS/ROCS X are commercial OpenEye products.

Before using code patterns, verify installed versions match. If versions differ:

• Python: pip show <package> then help(module.function) to check signatures

If code throws ImportError, AttributeError, or TypeError, introspect the installed package and adapt the example to match the actual API rather than retrying.

Shape Similarity

Search for compounds with similar 3D shape (and optionally chemical features) to a query molecule. Shape-based screening complements 2D fingerprint search: it can find scaffold-hopped compounds that ECFP4 misses (different scaffolds with similar shape). ROCS (OpenEye) is the industry-standard commercial tool; Open3DAlign (RDKit), USRCAT (Schreyer & Blundell 2012), and ShaEP are open-source alternatives. Modern best practice combines shape with color (chemical-feature similarity) via Tanimoto-Combo: matches share both shape and pharmacophore feature distribution.

For 2D fingerprint similarity, see chemoinformatics/similarity-searching. For pharmacophore search (discrete feature constraints), see chemoinformatics/pharmacophore-modeling. For 3D conformer generation, see chemoinformatics/conformer-generation.

Shape Method Taxonomy

Tool	Speed	Approach	Open-source	Fails when
ROCS / FastROCS (OpenEye)	Hardware/database/conformer-dependent; vendor reports millions of conformers/s for FastROCS	Gaussian shape + color	No	License and prepared database
ROCS X	Trillion-scale reaction/synthon space on Orion	FastROCS plus Bayesian-bandit sampling	No	Commercial cloud workflow
USRCAT	Very fast alignment-free descriptor comparison	Moment-based + atom types	Yes	Coarse approximation
Open3DAlign (RDKit)	Medium	MMFF atom-type/charge-weighted alignment	Yes	Requires compatible typed 3D structures
ShaEP	Benchmark on actual conformers/hardware	Field-based (shape + ESP)	Free binary; inspect license	Requires valid 3D structures and charges for ESP
ESPSim	Benchmark on actual workload	Electrostatic + shape	Yes	Limited public benchmarks
Phase-Shape (Schrödinger)	commercial	Shape + pharmacophore	No	Commercial
USR (original)	Very fast alignment-free comparison	Moment-based only	Yes	No atom-type information

Decision: Select a shape method by matched retrieval/enrichment performance, conformer preparation, throughput, licensing, and score semantics. USRCAT is useful as a fast prefilter; Open3DAlign provides an open alignment method; ROCS/FastROCS provide commercial shape/color workflows.

Decision Tree by Scenario

Scenario	Method	Notes
Large prepared library	USRCAT pre-filter + Open3DAlign rescore	Choose rescore budget from measured retrieval saturation
Production VS for scaffold hop	ROCS + color (commercial)	Industry standard
Scaffold hopping prospective	Open3DAlign with conformer ensemble	Shape + flexibility
Bioisostere replacement	ROCS color with neutral scoring	Pharmacophore-equivalent matches
Patent space carve-out	Shape constraint + 2D dissimilarity	Combine shape + dissimilar scaffold
Library diversity assessment	USRCAT k-nearest neighbor	Fast
Crystal-bound conformer template	Open3DAlign starting from co-crystal pose	Bioactive shape
Cross-target screening	Shape + pharmacophore feature	Combined screen

Tanimoto-Combo Scoring (ROCS Standard)

TanimotoCombo = Tanimoto_shape + Tanimoto_color

• Tanimoto_shape: volume overlap normalized
• Tanimoto_color: pharmacophore feature overlap

Each component is normalized from 0 to 1, so TanimotoCombo ranges from 0 to 2. It is a sum, not an average. Select follow-up thresholds from a relevant benchmark or enrichment study; a single cutoff is not portable across query preparation, color-force-field settings, and library composition.

USRCAT (Ultra-Fast Shape Recognition + Atom Types)

USRCAT (Schreyer & Blundell 2012) extends Ultrafast Shape Recognition (USR) with atom-type information. Each molecule is represented as a 60-dimensional moment vector (12 moments × 5 atom types).

Goal: Encode a molecule into the 60-D USRCAT moment vector and score similarity against another molecule for alignment-free shape search.

Approach: Parse the SMILES, add hydrogens, generate one 3D conformer with ETKDGv3, compute RDKit USRCAT descriptors, and compare descriptor vectors with RDKit's USR score.

from rdkit.Chem import rdMolDescriptors

mol = Chem.MolFromSmiles('CCO')
mol = Chem.AddHs(mol)
AllChem.EmbedMolecule(mol, AllChem.ETKDGv3())

descriptors = rdMolDescriptors.GetUSRCAT(mol)
# Returns numpy array of 60 floats: 12 USR moments x 5 atom types
# (all atoms, hydrophobic, aromatic, acceptor, donor)

similarity = rdMolDescriptors.GetUSRScore(desc1, desc2)

Speed: Descriptor calculation is linear in atoms and comparison is fixed-length, without pairwise alignment. Benchmark end-to-end throughput on the prepared conformer library before choosing a scale cutoff.

Limit: USRCAT is a coarse approximation. Predictive for analog identification; less precise for scaffold hopping.

Open3DAlign (RDKit)

Open3DAlign uses MMFF atom types and partial charges to find an atom-based 3D alignment:

Goal: Align a target molecule onto a query in 3D and score volume overlap with Open3DAlign.

Approach: Build 3D structures for query and target, run GetO3A, and call Align() to transform the probe in place. Score() is the unnormalized O3A objective, not a shape Tanimoto or ROCS TanimotoCombo. If a normalized shape similarity is required, compute 1 - rdShapeHelpers.ShapeTanimotoDist(...) after alignment.

from rdkit.Chem import rdMolAlign, rdShapeHelpers

query = Chem.MolFromSmiles('CCC(=O)Nc1ccccc1')
query = Chem.AddHs(query)
AllChem.EmbedMolecule(query, AllChem.ETKDGv3())

target = Chem.MolFromSmiles('CCC(=O)Nc1ccc(F)cc1')
target = Chem.AddHs(target)
AllChem.EmbedMolecule(target, AllChem.ETKDGv3())

O3A = rdMolAlign.GetO3A(target, query)
rmsd = O3A.Align()  # aligns target to query in place
o3a_score = O3A.Score()
shape_tanimoto = 1.0 - rdShapeHelpers.ShapeTanimotoDist(target, query)

GetO3A finds an alignment between conformers; Align() applies it and returns RMSD. Keep o3a_score and normalized shape_tanimoto distinct in outputs.

Open3DAlign vs ROCS: Open3DAlign is open-source and competitive on small benchmarks; slower than ROCS at scale.

Conformer-Ensemble Shape Searching

For each library molecule, generate ensemble of conformers; pick best-shape conformer:

Goal: Run shape-similarity search over a conformer ensemble per library molecule so bound-conformer-like shapes are recovered.

Approach: For each library molecule, add hydrogens, embed n_conf conformers with ETKDGv3, MMFF-optimize, score each conformer against the query with Open3DAlign, and keep the best score per molecule.

def shape_search_ensemble(query_mol, library_mols, n_conf=20):
    hits = []
    for target in library_mols:
        target = Chem.AddHs(target)
        ids = list(AllChem.EmbedMultipleConfs(target, numConfs=n_conf,
                                               params=AllChem.ETKDGv3()))
        if not ids:
            continue
        if not AllChem.MMFFHasAllMoleculeParams(target):
            continue
        optimization = AllChem.MMFFOptimizeMoleculeConfs(target)
        if any(status != 0 for status, _ in optimization):
            continue

        scores = []
        for c in range(target.GetNumConformers()):
            O3A = rdMolAlign.GetO3A(target, query_mol, prbCid=c)
            O3A.Align()
            scores.append(1.0 - rdShapeHelpers.ShapeTanimotoDist(
                target, query_mol, confId1=c,
            ))
        if scores:
            hits.append((target, max(scores)))
    return sorted(hits, key=lambda x: x[1], reverse=True)

Critical: Results depend on conformer coverage. Use an ensemble sized and validated for the library and query rather than assuming one conformer is representative.

ESP Similarity (Electrostatic)

ShaEP and ESPSim extend shape with electrostatic surface potential overlap. For ESP-relevant pharmacophores (binding pockets with strong electrostatics):

shaep -q query.mol2 target.mol2 -s aligned_hits.sdf similarity.txt

ESP scoring catches electrostatic-equivalent bioisosteres that pure shape misses (carboxylate vs tetrazole same charge).

Shape vs ECFP4 Complementarity

Shape result	ECFP4 result	Interpretation
High	High	Close analog candidate
High	Low	Scaffold-hop candidate
Low	High	Similar 2D chemotype in a different sampled shape
Low	Low	Unrelated by these representations

Calibrate “high” and “low” on a task-relevant reference set; do not treat the illustrative function defaults below as universal scientific cutoffs.

The shape >> ECFP4 quadrant is the scaffold-hopping gold:

Goal: Identify scaffold-hop candidates that are 3D-shape-similar but 2D-chemotype-dissimilar to the query.

Approach: Run the conformer-ensemble shape search, keep hits above a shape Tanimoto cutoff, then retain only those whose ECFP4 Tanimoto to the query is below an ECFP4 dissimilarity cutoff.

# These thresholds are repository starting defaults only; calibrate both on a
# task-relevant active/decoy or retrieval benchmark before making decisions.
def scaffold_hop_candidates(query_mol, library, shape_threshold=0.7,
                            ecfp_threshold=0.5):
    shape_hits = shape_search_ensemble(query_mol, library)
    candidates = []
    for target, shape_score in shape_hits:
        if shape_score >= shape_threshold:
            ecfp_sim = ecfp_tanimoto(query_mol, target)
            if ecfp_sim < ecfp_threshold:
                candidates.append((target, shape_score, ecfp_sim))
    return candidates

Per-Tool Failure Modes

USRCAT -- false positive on small molecules

Trigger: Library has many fragment-sized compounds.

Mechanism: USRCAT moments dominated by overall shape; small molecules look "similar" if shape resemble.

Symptom: Many fragment hits; not pharmacophore-relevant.

Fix: Calibrate size/property filters on the retrieval task and rescore selected hits with an alignment or feature-aware method.

Open3DAlign -- slow on large library

Trigger: Million-compound library, full alignment.

Mechanism: Open3DAlign is iterative; O(N) per molecule.

Symptom: Hours of compute.

Fix: Pre-filter with USRCAT and choose the rescore budget from measured throughput and retrieval saturation.

Shape only -- wrong stereochemistry match

Trigger: Mirror-image of correct binder.

Mechanism: Shape-only scoring may insufficiently penalize stereochemical alternatives even though a rigid rotational overlay is not generally invariant to mirror reflection.

Symptom: Enantiomer of inactive scores as hit.

Fix: Validate hits by 3D pose; check stereochemistry.

ROCS color -- bioisostere missed

Trigger: -COOH replaced by -SO3H or tetrazole.

Mechanism: Default color types may not equate these bioisosteres.

Symptom: Known bioisostere doesn't score high.

Fix: Validate the color-force-field treatment for the bioisostere and compare shape, color, and pharmacophore evidence separately.

Conformer not bioactive

Trigger: Library compound generated conformer is not the bound conformation.

Mechanism: ETKDGv3 generates plausible conformers; bound conformer may be higher energy.

Symptom: Known active doesn't shape-match query.

Fix: Use larger conformer ensemble; weight by Boltzmann; or use CREST + GFN2-xTB for high-quality sampling.

Field-based methods slower

Trigger: ShaEP or ESPSim on production library.

Mechanism: Field-based methods compute Gaussian fields per molecule.

Symptom: Field calculation or alignment dominates runtime on the prepared library.

Fix: Use as second-stage rescore; not primary screen.

Reconciliation: Shape vs Pharmacophore

Aspect	Shape	Pharmacophore
Representation	Volume distribution	Discrete features in space
Captures	Overall bulk	Interaction-relevant features
Speed	Fast (USRCAT) to medium (Open3DAlign)	Fast
Specificity	Task- and query-dependent	Task- and feature-definition-dependent
False positive rate	Measure on a matched benchmark	Measure on a matched benchmark
Best for	Scaffold hopping initial	Scaffold hopping refinement

Shape and pharmacophore searches make different approximations. Compare them alone and in sequence on a matched active/decoy or retrieval benchmark before assigning recall/precision roles.

Common Errors

Symptom	Cause	Fix
Open3DAlign RMSD is near 0	Near-exact O3A alignment	Treat as a successful alignment; evaluate the O3A and shape scores separately
USRCAT vector all zeros	Mol has no 3D coords	Generate conformer first
Shape Tanimoto > 1	Raw O3A or TanimotoCombo mislabeled as shape Tanimoto	Shape Tanimoto is 0-1; O3A is unnormalized and ROCS TanimotoCombo is 0-2
ROCS very slow	Sequential processing	Use parallel batching
Shape match but no docking pose	Wrong binding pose	Use docking on top shape hits, not shape alone
Missing co-crystal template	Apo or AlphaFold-only structure	Use ligand-based pharmacophore + shape
ShaEP returns no hits	Strict tolerance	Loosen overlap thresholds

References

• Hawkins et al., J. Med. Chem. 50:74-82 (2007), DOI 10.1021/jm0603365 -- ROCS virtual-screening comparison.
• Schreyer AM, Blundell T. J. Cheminformatics 4:27 (2012) -- USRCAT (DOI 10.1186/1758-2946-4-27).
• Vainio, Puranen & Johnson, J. Chem. Inf. Model. 49:492-502 (2009), DOI 10.1021/ci800315d -- ShaEP.
• Tosco, Balle & Shiri, J. Comput. Aided Mol. Des. 25:777-783 (2011), DOI 10.1007/s10822-011-9462-9 -- Open3DALIGN.
• RDKit O3A API: https://www.rdkit.org/docs/source/rdkit.Chem.rdMolAlign.html
• RDKit shape API: https://www.rdkit.org/docs/source/rdkit.Chem.rdShapeHelpers.html
• ShaEP official documentation/examples: https://cheminformatics.fi/
• OpenEye ROCS X product documentation: https://www.eyesopen.com/rocsx

Related Skills

• chemoinformatics/molecular-io - Parse query and library
• chemoinformatics/conformer-generation - Generate 3D conformer ensembles
• chemoinformatics/similarity-searching - 2D similarity comparison
• chemoinformatics/pharmacophore-modeling - Pharmacophore alternative
• chemoinformatics/scaffold-analysis - 2D scaffold analysis
• chemoinformatics/virtual-screening - Shape as pre-filter to docking