---
name: bio-shape-similarity
description: Performs 3D shape-based similarity searching using ROCS (OpenEye), USRCAT (ultra-fast), Open3DAlign (RDKit), ESPSim (electrostatic), and ShaEP with explicit handling of Tanimoto-Combo (shape + color), shape vs ECFP4 complementarity, conformer-ensemble searching, alignment optimization, and scaffold hopping. Use when searching for shape-mimicking compounds with different scaffolds, identifying bioisosteric replacements, prospective scaffold hopping, or expanding hit series beyond 2D similarity.
tool_type: python
primary_tool: RDKit
---

## 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.

```python
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.

```python
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.

```python
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):

```bash
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.

```python
# 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