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Can I calculate binding affinities with Schrödinger software?

Computing accurate absolute, or even relative, binding energies is an extremely challenging task.

The GlideScore or the docking score is an estimate of the binding affinity, but it is only accurate to a few kcal/mol. Its use is therefore limited to distinguishing actives from inactives (e.g. nanomolar from micromolar).

Prime MM-GBSA and MacroModel Embrace are two programs that allow receptor flexiblity, and we have had some success in particular with Prime MM-GBSA for rank-ordering congeneric series of ligands. Both of these are molecular mechanics applications.

If you have a set of known actives, you could develop a custom scoring function, based on the GlideScore, its components, or other descriptors (e.g., from MacroModel Embrace or Prime MM-GBSA) that is optimized for binding energy predictions with a particular receptor. By fitting the scoring model to experimental binding data, you might be able to get better binding-energy prediction, at the cost of loss of transferability to other systems. This can be done with Liaison, for example, or you can use Strike or Canvas to fit a model.

Another option for calculating the relative binding affinity of related compounds is to run an FEP molecular dynamics simulation with Desmond, to mutate one structure into another. You can set up FEP jobs to mutate ligand structures and protein structures in Maestro. Monte Carlo simulations of such mutations are also available with MCPRO+.

Keywords: GlideScore, Binding energy, binding affinity, receptor conformations, induced fit effects

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