Predicting protein-ligand binding free energies is a crucial aim of computational structure-based drug design (SBDD) — improved accuracy in binding free energy predictions could significantly reduce costs and speed project timelines in lead discovery and optimization. The recent development and validation of advanced free energy calculation methods represents a major step towards this goal. Accurately predicting the relative binding free energy changes of modifications to ligands is especially valuable in the field of fragment-based drug design, since fragment screens tend to deliver initial hits of low binding affinity that require multiple rounds of synthesis to gain the requisite potency for a project. In this study, we show that a novel free energy calculation protocol, FEP+, which was previously validated on drug-like lead compounds, is suitable for the calculation of relative binding strengths of fragment-sized compounds as well. We study five pharmaceutically relevant targets wih a total of more than 50 fragments and find that the FEP+ methodology delivers highly accurate predictions of relative inhibitor strengths, with R2 values generally greater than 0.5 compared to experimental data and mean errors less than 1.0 kcal/mol in all cases, affording significant improvements over other com-putational methods. This validation indicates that an unparameterized physics-based approach using molecular dynamics has the requisite predictive power to impact fragment-based affinity optimization projects.

Fragment-based free energy perturbation

249th National Meeting (2015)

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