An open-source molecular builder and free energy preparation workflow

Automated free energy calculations for the prediction of binding free energies of congeneric series of ligands to a protein target are growing in popularity, but building reliable initial binding poses for the ligands is challenging. Here, we introduce the open-source FEgrow workflow for building user-defined congeneric series of ligands in protein binding pockets for input to free energy calculations. For a given ligand core and receptor structure, FEgrow enumerates and optimises the bioactive conformations of the grown functional group(s), making use of hybrid machine learning/molecular mechanics potential energy functions where possible. Low energy structures are optionally scored using the gnina convolutional neural network scoring function, and output for more rigorous protein-ligand binding free energy predictions. We illustrate use of the workflow by building and scoring binding poses for ten congeneric series of ligands bound to targets from a standard, high quality dataset of protein-ligand complexes. Furthermore, we build a set of 13 inhibitors of the SARS-CoV-2 main protease from the literature, and use free energy calculations to retrospectively compute their relative binding free energies. FEgrow is freely available at https://github.com/cole-group/FEgrow, along with a tutorial.