This option can be found in the Docking -> De Novo Tools -> Hybridize menu.

Hybridize Method

Overview

The Hybridize method generates new ligand ideas by matching a bond in two aligned ligands and creating chimeric molecules by exchanging the substituents on either side of that bond.

The method operates on already aligned 3D ligands and is typically applied to:

• Docking hitlists
• X-ray or cryo-EM resolved ligands from a Pocketome entry
• Other pre-aligned ligand tables

The same table may be used as both inputs to generate cross-hybrids within a single ligand set.

Typical Workflow

1. Provide one or two ligand tables as input.
2. Identify bonds that can be matched based on 3D geometry.
3. Generate chimeras by swapping fragments across the matched bond.
4. Review the generated chimeras.
5. Select chimeras and re-dock them.
6. Compare docked chimeras to parent ligands.

Inputs

Hitlist 1

A table of aligned 3D ligands used as the first source of parent molecules.

• Typically a docking hitlist produced by ICM docking.
• May also be an aligned ligand table, for example Pocketome ligands.
• Ligands must contain valid 3D coordinates.
• If an IX column is present, it is propagated to the output as IX1.

Hitlist 2

A table of aligned 3D ligands used as the second source of parent molecules.

• Same requirements as Hitlist 1.
• May be identical to Hitlist 1 to generate cross-hybrids.
• If an IX column is present, it is propagated to the output as IX2.

Distance Tolerance

Maximum allowed RMSD, in angstroms, between the atoms adjacent to the matched bond in the two ligands.

• Controls spatial overlap of the local bond environments.
• Lower values produce fewer, higher quality hybrids.
• Higher values increase the number of generated chimeras.

Angle Tolerance

Maximum allowed rotation angle, in degrees, between the matched bonds.

• Measures bond orientation compatibility.
• Smaller values enforce stricter matching.
• Larger values allow more flexible recombination.

Method Description

Bond Matching

Bonds are matched between ligands based on bond type and local 3D geometry. Only bonds satisfying the distance and angle tolerances are considered.

Fragment Definition

Each matched bond divides a ligand into two fragments, defining substituents on either side of the bond.

Chimerization

Fragments from ligand A and ligand B are recombined across the matched bond to generate new hybrid molecules.

Output: Chimeras Table

Each row in the Chimeras table corresponds to one matched bond pair and its resulting hybrid molecules.

Fragment Columns

• R1A, R2A: Fragments from ligand A on either side of the matched bond.
• R1B, R2B: Fragments from ligand B on either side of the matched bond.

Index Columns

• ix1, ix2: Indices of the parent ligands in the input tables.
• IX1, IX2: Original ligand indices from docking hitlists, if present.

Geometry Quality Metrics

• Distance: RMSD of atoms adjacent to the matched bond.
• Angle: Rotation angle between the matched bonds.

Hybrid Molecules

• H1, H2: Hybrid molecules generated by fragment exchange.

Browsing Behavior

When docking hitlists are used as input, the Chimeras table is browsable. As the cursor moves through the table, the two parent ligands corresponding to each row are displayed for visual inspection.

Practical Notes

• Looser tolerances generate more hybrids for exploratory screening.
• Stricter tolerances favor higher confidence hybrids.
• Re-docking is recommended to validate binding mode inheritance.