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 adapted from the 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 OpenEye RBFE-NES method quickly transitions through intermediate states and samples many short trajectories, making it remarkably parallelizable.
- Tested: The method has been tested on several targets, including CDK2, PTP1B, Jnk1, p38, Thrombin, MCL1, Bace, Hunt13, and Tyk2. Industry standard Open Force Field and GROMACS are available in the methodology.
- Accurate: Using Kandall’s tau measurement, OpenEye’s method has comparable accuracy to RBFE benchmarks from literature for GAPSYS (2020) and FEP (JACS 15) datasets. Additionally, a robust linear NES-based model shows no significant differences on aggregate performance compared to experimental methods.
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, before NES is performed a fast evaluation can be done for system setup and end-point equilibration.
- 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 several thousand NES runs for only a few hundred dollars. NES is a very cost-effective free cloud native 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