Release Highlights 2025.2

Small Molecule Discovery Suite Highlights

pKa Prediction Floes Package

The new pKa Prediction Floes Package predicts the dominant ionization states and pKas of small molecules. The ionization state of a drug candidate affects crucial physical properties including solubility, membrane permeability, target binding affinity, and ADMET. Therefore, using the correct ionization state for a given pH environment is very important to get accurate results from many computational methods, especially binding free energy calculations. The Generate Ionization States and Calculate LogD Floe predicts the dominant ionization state at a specified pH. The pKa Exploration Floe Floe provides a detailed report showing the titration curves and distributions of ionization states at different pH values.

Figure 1. The floe report identifies all ionizing groups and includes the titration curve, macrostate population curves, logD versus pH, microstate population curve, and micro- and macro-pKa reactions with tautomer ratios. This animated figure shows each aspect of the report and the changes of various features in relation to others. Note: to view the animation again, please refresh your browser after the animation has finished. Individual parts of the floe report can be found in the pKa Prediction Report within the pKa Exploration Floe tutorial.

Cryptic Pocket Detection Floes Package

Ligandability Assessment for Pocket Ranking and Representative Conformation Selection

Cryptic pockets are ranked by a ligandability prediction model which is trained and validated on a curated, nonredundant dataset consisting of diverse ligand-binding pockets. The unnormalized total score and normalized ligandability score, along with the significance score, are then computed for each pocket found during cryptic pocket detection.

Figure 2. The pocket ligandability score prediction.

Figure 3. The assessment of significance score (Bayes factor) for the normalized pocket ligandability score.

The new Ligandable Medoids Extraction Floe extracts an ensemble of ligandable medoid conformations for a selected pocket. A binding site view can be generated for pockets detected by probe binding analysis techniques after specifying “DUM” (the component representing xenon-occupancy grids for a pocket) as a ligand in the binding generation option.

Figure 4. The ligandability score and ranking for cryptic pocket predictions.

Improved Time and Cost Efficiency for Dynamic Probe Binding Analysis

The performance of the Dynamic Probe Binding Analysis Floe has significantly improved, now being ten times faster and five times lower in cost.