Many structure-based drug design methods, including free energy perturbation (FEP+), require accurate, atomic-level detail of protein-ligand complexes in order to perform optimally; consequently, the domain of applicability of SBDD is limited by the availability of high-resolution crystal structures. Often a highly sequence-similar structure to the target of interest has been solved in complex with a different ligand, so only protein sidechain and small loop motions are required to build a realistic model of the target; however, exploring the relative energetics of all possible protein motion is infeasible. Here we present a new method, IFD-MD, that addresses these challenges using a combination of water thermodynamics, empirical scoring functions, implicit solvent force field energies and explicit solvent metadynamics trajectories. We applied IFD-MD to predicting the binding modes of over 400 published co-crystal structures using the complex structure of a highly dissimilar ligand as a starting point. In cases where binding affinity data were available we demonstrate the ability to predict retrospectively those binding affinities with FEP+ using the cross-docked binding site conformation produced by IFD-MD, demonstrating that these cross-docked structure are suitable for structure-based drug design. In the second part of this work we demonstrate the applicability of IFD-MD to refinement of homology models. IFD-MD reliably identifies protein-ligand binding poses when the sequence identity between the target protein and template is greater than 40%. Last, we show some early examples of impact of IFD-MD in real-world drug discovery programs, where it is applied in conjunction with FEP+ for prospective prediction of binding affinity for a target where no co-crystals are available. Taken all together, we demonstrate the potential of IFD-MD to increase significantly the impact of structure-based drug design.

Expanding the domain of applicability of structure-based drug design with IFD-MD

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.