Release Highlights 2026.2

Small Molecule Discovery Suite

Classic Floes

The BROOD - 3D Fragment Replacement Floe in Classic Lead Optimization Floes has been substantially expanded with three query selection types. The classic Brood fragment replacement remains available. A new option has been added to select atoms to keep while performing fragment replacement on the rest of the molecule. This option can be set to select no atoms and replace the whole molecule for complete de novo design.

Figure 1. EZH2 inhibitor design, with no part of the molecule selected to keep. Fragments are automatically identified for bioisosteric replacement both individually and simultaneously.

After running the BROOD - 3D Fragment Replacement Floe, the resulting hit list is ranked based on 3D similarity to the reference molecule. Figure 2 shows some examples.

Figure 2. The EZH2 query molecule is shown in green. The blue molecule (top right) shows an example of every part of the query being replaced. The yellow molecule (bottom left) shows a hit with good overlap with the query. The purple molecule (bottom right) shows an example of a hit with fragment 3 replaced.

The BROOD - 3D Fragment Replacement Floe also supports linking and cyclization. The user selects atoms that need a linker. This mode supports linking fragments or cyclization if the selected atoms are in the same molecule.

Figure 3. Examples of linking and cyclization. The query molecule is shown in green. The pink atoms indicate linking points. The query requires two parts to be selected to be replaced in the cyclization; these parts are shown using the ball-and-stick representation. The other molecules are examples of hits that have been cyclized.

ROCS X Floes

Several features have been introduced to the ROCS X Floes to enable more customization. These capabilities include support for any ROCS-type query, including those without a ligand. Queries can be generated with OpenEye tools for a pocket of a protein, enabling virtual screening on the trillions scale without a known ligand. In addition, ROCS X now also supports custom color force fields.

Figure 4. Shape query used for virtual screening (left). The score distribution of Tanimoto combo versus shape Tanimoto for the ROCS X hit list is shown on the right. The 2D and 3D depictions show the top hit molecule.

On-the-fly filtering has made the ROCS X Floes more efficient because filters are evaluated as products are enumerated. Filters include 2D similarity for increased diversity and SMARTS matching, useful for requiring or excluding specific substructures.

Large Scale Floes

Collection preparation in Large Scale Floes is now more efficient. Conformer generation is the most computationally intense part of the Prepare Giga Collections Floe. Using Omega with Thompson sampling makes the step 2-3X faster. In addition, Gigadock collections, with larger conformer ensembles, are now optional. By default, only the FastROCS collection will be created. This makes preparing custom collections for Large Scale Floes or Custom Molecule Search Databases more computationally efficient.

The FastROCS Plus Floe now supports a much broader range of screening inputs. All ROCS query types can now be used as input, including mixed input queries with molecule, shape, and pocket queries.