Lead Optimization in Orion® using Relative Binding Free Energy with Non-Equilibrium Switching (RBFE-NES)
When optimizing leads, you now can perform RBFE-NES calculations directly within the easy-to-use Orion® molecular design environment.
Built on trusted science, Orion’s RBFE-NES tools help you estimate free energy binding affinities based on the calculation of thermodynamic work along fast, non-equilibrium alchemical paths.
Like all Orion® solutions, the RBFE-NES tools are built natively to run on Amazon Web Services (AWS), so they seamlessly scale to your needs while remaining cost- and time-efficient.
Snapshots from equilibrium Molecular Dynamics (MD) runs are selected as initial conditions to run Non-Equilibrium Switching (NES) calculations. In the picture, the ligand A in solution (Unbound State) is quickly alchemically mutated into ligand B (and vice versa). This process is highly parallelizable in Orion and gives you the fastest and most cost-effective relative binding free energy calculations for your target-ligand complexes.
- Proven: The RBFE-NES tools within Orion® are modled after the GROMACS-based Non-Equilibrium Switching (NES) work done by Vytautas Gapsys in the Bert L. DeGroot lab at the Max Planck Institute for Biophysical Chemistry (Gapsys et al., Chem. Sci. 2020, 11, 1140-1152). The method in Orion® includes proprietary OpenEye methods for system pre-equilibration and chimeric-molecule calculation.
- Parallelizable: The Orion RBFE-NES method quickly transitions through intermediate states and samples many short trajectories, making it remarkably parallelizable.
- Tested: The method has been validated on a number of datasets, including CDK2, PTP1B, Jnk1, p38, Thrombin, MCL1, Bace, and Tyk2. Open Force Field (OpenFF) and GAFF small molecule force field are available.
- Accurate: Kandall’s tau correlations show OpenEye’s method has comparable accuracy to RBFE benchmarks from literature for GAPSYS (2020) and FEP (JACS 15) datasets and no significant differences in aggregate performance.
- Innovative: The Orion RBFE-Mapper utilizes OpenEye's proprietary algorithm to build optimal set of edges for efficient binding free energies calculations.
Orion’s RBFE mapper prepares a set of ligands for Non-Equilibrium Switching (NES) by creating an optimal set of “edges”, which are individual transformations of one ligand into another. These edges allow NES to run efficiently by building up a map of transformations necessary to estimate the binding free energies of the entire ligand set. Orion’s RBFE mapper (version 2021.2) considers both Maximum Common Substructure (MCS) similarities and OpenEye’s proprietary ROCS (shape and color) Score in optimizing the edge selection process.
Ease of Use
- Intuitive: The standard Orion® graphical workflow engine, Floe, is used to set up RBFE-NES calculations, letting you quickly get up and running in a familiar environment.
- Familiar: System set-up and end-point equilibration for RBFE-NES is nearly identical to what Orion® users are accustomed to for short-trajectory molecular dynamics.
- Unique: Unlike other methods, the system setup and equilibration needed for NES can be used for faster and cheaper evaluations to triage ligands prior to the NES calculation itself.
- Integrated: Easily combine other ligand- and structure-based methods available in Orion® with your relative binding free energy NES calculations to build the best processes for your drug discovery modeling needs.
Scalable and Efficient
- Cloud-based: Orion® helps you efficiently run thousands of fast NES calculations in parallel by leveraging AWS high-performance computing. You are no longer constrained by time or hardware resources.
- Nimble: Orion's proprietary scheduler automatically figures out how to get more GPUs by drawing on available AWS spot instances.
- Efficient: While costs and times vary, test cases show that within a few hours you can run dozens of ligands for only a few hundred dollars. NES is a very cost-effective (cloud native) free energy calculation method.
- Fault-tolerant: Automatic scaling groups and dynamic allocation means your calculations will run to completion, even if AWS spot instances are sparse.
Read more about the science behind Orion’s RBFE-NES
Watch OpenEye’s webinar presentation about Orion’s RBFE-NES method