Structural datasets for a large-scale retrospective affinity prediction of macrocyclic ligands across five diverse targets (KRAS, PCSK9, MCL-1, JAK2, Cyclin A/B).
This repository contains the structural inputs associated with our retrospective validation of Free Energy Perturbation (FEP+) on beyond-Rule-of-5 (bRo5) macrocycles and cyclic peptides.
Rational design of macrocycles is complicated by restricted conformational entropy, closed-loop topologies, and kinetic trapping. This dataset comprises a set of 240 macrocyclic ligands spanning five diverse therapeutic targets:
- KRAS
- PCSK9
- MCL-1
- JAK2
- Cyclin A/B
inputs/target_name: Contains the protein receptor structures (.pdb), the aligned macrocyclic ligands (.sdf) and the force field parameters (.opls).data_summary.csv: The master file containing all experimental affinities, FEP+ predicted absolute affinities and calculated errors.
Calculations were performed using the Schrödinger Suite (Release 2025-4). Advanced sampling protocols, including Replica Exchange with Solute Tempering (REST) and Grand Canonical Monte Carlo (GCMC) for hydration site analysis, were employed to overcome the high-energy kinetic barriers inherent to macrocyclic topologies.
If you utilize this dataset for benchmarking your own force fields or free energy methodologies, please cite:
Awoonor-Williams et al. "De-risking Affinity Optimization for Macrocycles and Cyclic Peptides: High Precision Free Energy Simulations across Five Diverse Targets", J. Chem. Inf. Model., 2026 DOI:10.1021/acs.jcim.6c01122.
This dataset is provided under the MIT License.