Protein-ligand docking
An excellent way to build up knowledge about the binding pocket and collect insights about the key intermolecular interactions to validate the binding mode hypothesis, it can also form the basis for a virtual screen to identify new active compounds.
To conduct a successful ligand-protein docking, a careful protein preparation is recommended, particularly when there is very little information available about the protein target. This could involve modeling and refinement of the structure and checking that the correct residues are in the right places on the active site for the ligands. The docking protocol can be easily validated when there is an available holo-structure by removing the ligand from the complex and carry out docking to ensure the generation of reasonable docked poses. However, if there are no bound structures available, you can perform a pocket analysis to confirm or identify the most druggable binding site(s) and then dock a known ligand for the target to calculate the energies and electrostatics for the protein-ligand interactions, to make sure you have identified poses that make sense.
This preparatory work is essential and requires expert knowledge, experience and skills. Cresset Discovery Solutions has proved know-how and can support you on your project, successfully identifying new active compounds, which enables time and cost savings.
Molecular docking in Flare™ uses Lead Finder™ that combines a genetic algorithm search with local optimization procedures.1 Flare provides many flavors of docking experiments, allowing you to:
- Predict the 3D structure of protein-ligand complexes by docking one or multiple flexible ligands to a single static protein structure.
- Tackle the protein flexibility by docking your non-covalent and/or covalent ligand(s) against an ensemble of alternative conformations of the receptor/protein.
- Set docking constraints to bias poses to include key protein-ligand interactions.
- Use a ligand template with a known bound pose to seed a docking of ligand(s) that share a common substructure, such as congeneric series.
- Predict the binding pose and interactions of covalent inhibitors, choosing your preferred covalent warhead, against to a particular residue in the protein.
- Stroganov O.V. et al., Lead Finder: an approach to improve accuracy of protein-ligand docking, binding energy estimation, and virtual screening, J. Chem. Inf. Model. 2008, 48(12), 2371-2385.
Protein-protein docking
Many cellular functions, such as signal transduction, regulation and protein synthesis, are dependent on a relevant assembly of multiple proteins to become biologically functional. Protein-protein molecular docking is a powerful computational approach to predict protein complexes at the atomic level and subsequently give insight into the mechanisms that underlie their biological function(s). Protein-protein docking is gaining more versatility due to the increasing availability of structural information on targets from X-ray crystallography or cryo-electron microscopy methods.
By capturing protein shape, electrostatics, and local dynamics using the JabberDock algorithm,1 Flare provides a fast and flexible protein–protein docking tool that could support your projects by accelerating the design of protein binders and drugs for a wide variety of targets. In addition to find matches of high shape complementarity between the proteins, it also incorporates protein dynamics to improve docking reliability and identification of potential binding-induced conformational changes.
To conduct a successful protein-protein docking, a careful analysis of the multiple protein assemblies generated is recommended, namely for challenging systems such as those with more than one relevant state available (e.g. active vs. inactive or open vs. closed) to be used as starting structure for docking, or systems with highly flexible protein shapes. Pocket detection and hot spots mapping of protein surfaces, combined with modeling and visual analysis to identify matchable hydrophobic regions from the two proteins/partners, could be used to refine the final protein-protein docking models.
The figure below shows the results of a protein-protein docking experiment performed in Flare to predict the binding of a monoclonal antibody against an extracellular human tissue factor. Comparing the results with a crystallographic structure of the complex, we can see that the binding interface of both proteins were rapidly and accurately indicated. The discrepancy observed in the remaining/exposed region of the tissue factor is reasonably expected due to the large, extended and dynamic shape of this part of the protein structure.
- L.S.P. Rudden, M.T. Degiacomi, Protein Docking Using a Single Representation for Protein Surface, Electrostatics, and Local Dynamics, J. Chem. Theory Comput. 2019, 15, 9, 5135–5143
