Free Energy Perturbation (FEP): Another technique in the drug discovery toolbox
Introduction When I first started using CHARMM over 20 years ago as a PhD student, I regularly came across references ...
I am delighted to announce the release of Flare V3 which enables computational and medicinal chemists to access new scientific capabilities which will extend the range of structure-based design methods available to them. Join me in a tour of the most significant new features of this major release.
As anticipated in the recent sneak peek and alchemical free energy calculations blog post, Flare V3 features a fully integrated and user-friendly interface to Free Energy Perturbation (FEP) calculations, developed in collaboration with Dr Julien Michel at the University of Edinburgh, UK. The best open-source tools (such as AMBER tools, OpenMM, an extended and improved version of LOMAP, Sire and BioSimSpace) have been combined with Cresset expertise in delivering intuitive software. The result is a robust, user-friendly, fully validated and accessible implementation of FEP for predicting relative binding affinity changes within a congeneric ligand series using ‘alchemical’ transformations.
Figure 1: Flare V3 features a robust, validated and user-friendly interface to FEP calculations.
Ligand docking has been significantly overhauled in Flare V3.
Covalent docking is a new module enabling you to predict the binding pose and interactions of covalent inhibitors. This class of ligands derives their activity by forming a covalent bond with the target while making at the same time a network of non-covalent interactions with the active site of the protein.
Running a covalent docking experiment in Flare is easy. You choose the ligands you want to dock, arm them with an appropriate covalent warhead, such as one of those shown in Figure 2, choose the protein you want to dock your ligands into, and tell Flare which covalent residue the ligands should bind to, choosing from Cys, Lys, Thr and Tyr.
Figure 2. Covalent warheads supported by Flare V3.
The docked ligands will be added to the Ligands table, each associated with a number of poses to explore (Figure 3).
Figure 3. New covalent docking in Flare V3.
Template docking is useful when you know the pose of a ‘template’ ligand and want to use this information to bias the docking results for congeneric compounds. The molecules to be docked are aligned by substructure to the template ligand, and the aligned conformation is used to seed the docking run, generally leading to improved docking results, as shown in Figure 4. In Flare V3, the template docking option is available for both traditional docking and ensemble docking.
Figure 4. Template docking (right) generally leads to improved docking results when the experimental pose of a ‘template’ ligand is known. Left: Accurate but slow docking. Right: Template docking.
Significant improvements have been made to the underlying Lead Finder docking algorithm. The ‘Accurate’ and ‘Very Accurate’ docking calculation methods now include a new customizable option which performs repeat docking runs, keeping the best poses overall for each ligand, thus generating improved docking results with slightly longer calculation times. Docking constraints can be added to selected protein atoms to ensure that docked poses match relevant hydrogen bond interactions with the active site of the protein.
The conformation hunt and molecular alignment features of Forge™, now included in Flare V3, enable you to carry out ligand-based alignments using ligand fields, shape properties or a common substructure. This is useful to make meaningful comparisons across chemical series, and to generate sensible poses for each ligand within the protein active site, which provide excellent starting points for Electrostatic Complementarity™ and FEP calculations.
Figure 5. Ligand-based alignment in Flare V3 generates sensible poses providing useful starting points for further calculations.
You can now perform Molecular Dynamics (MD) experiments using OpenMM to study the conformational changes of proteins and assess the stability of protein-ligand complexes. To set-up a MD calculation in Flare V3, just press the Dynamics button in the Protein tab, review the set-up of the calculation and press start when ready. You can either use local GPUs/CPUs or rely upon the seamless connection to remote calculation resources offered by the Cresset Engine Broker™ to speed up the calculation. Results are displayed in the Dynamics dock where playback of the simulation is controlled (Figure 6). MD snapshots can be easily added to the Flare project and used as the starting points for further experiments, such as ensemble docking or FEP calculations.
Figure 6. Results of a MD experiment in Flare.
More than 70 new Python classes, calculations, callbacks, methods and properties have been added to Flare V3. New features include functionality to run FEP and MD calculations using Flare’s command-line binary pyflare and python scripts.
As well as the additions detailed above, Flare V3 also includes more than 100 new and improved features, such as: