Conformer Alignment

Superimpose 3D conformers of a retrieved molecule onto the query molecule to visualise how well their shapes and pharmacophoric features overlap.

How it works

• A set of low-energy 3D conformers is generated for both the query and the probe (retrieved) molecule.
• Each probe conformer is aligned onto each query conformer using the selected alignment method.
• The best-scoring pairs are returned with their RMSD, energy, and alignment score.
• You can interactively switch between conformer pairs in the 3D viewer to inspect the overlap.

Alignment methods

MCS (Maximum Common Substructure)

Identifies the largest shared substructure between the query and probe molecules, then aligns conformers by superimposing the matched atoms.

• Finds the maximum common substructure (MCS) between two molecules using RDKit's FMCS algorithm
• Generates 3D conformer ensembles for both the query and probe molecules
• Aligns each probe conformer onto each query conformer using the MCS atom mapping
• Reports RMSD computed over the matched atom pairs
• Best suited when molecules share a clear common scaffold

MCS Constrained

Uses the MCS core as a rigid constraint during conformer generation, then aligns on the constrained atoms. This produces tighter overlaps on the shared scaffold.

• Identifies the MCS core the same way as the standard MCS method
• Generates probe conformers with the core atoms constrained to match the reference geometry (ConstrainedEmbed)
• Non-core atoms are energy-minimised while the core stays fixed
• Yields lower RMSD on the core but may differ more in peripheral regions
• Useful when preserving the binding-pose geometry of the shared scaffold is critical

Open3DAlign

An unsupervised 3D alignment method that optimises the overlap of molecular volumes and force-field atom types without requiring a predefined atom mapping.

• Uses the Open3DAlign algorithm implemented in RDKit (GetO3A)
• Automatically determines the optimal atom-atom mapping based on MMFF94 atom types
• Maximises a score that combines steric (shape) and electrostatic overlap
• Does not require a common substructure — works for structurally diverse molecule pairs
• Returns an alignment score and RMSD for each conformer pair

When to use which method?

Sources

• RDKit Molecular Alignment Module — rdkit.Chem.rdMolAlign Docs
• Landrum, G. 3D MCS-based alignment with RDKit. RDKit Blog, 2022. Link
• Tethered minimization of small molecules with RDKit. Discngine Blog, 2019. Link