Computational approaches for binding affinity prediction are most frequently demonstrated through cross-validation within a series of molecules or through performance shown on a blinded test set. Here, we show how such a system performs in two realistic applications: 1. An iterative, temporal lead optimization exercise, and 2. A hybrid strategy that leverages diversified information as input. In the first evaluation, a series of gyrase inhibitors with known synthetic order formed the set of molecules that could be selected for "synthesis." Beginning with a small number of molecules, based only on structures and activities, a model was constructed using the newly developed Surflex-Quantitative Modeling (QMOD) approach. Compound selection was done computationally, each time making five selections based on confident predictions of high activity and five selections based on a quantitative measure of three-dimensional structural novelty. Compound selection was followed by model refinement using the new data. Iterative computational candidate selection produced rapid improvements in selected compound activity, and incorporation of explicitly novel compounds uncovered much more diverse active inhibitors than strategies lacking active novelty selection.

For the second evaluation we present a hybrid structure-guided strategy that combines molecular similarity, docking, and multiple-instance learning such that information from protein structures can be used to inform models of structure-activity relationships. The Surflex-QMOD approach has been shown to produce accurate predictions of binding affinity by constructing an interpretable physical model of a binding site with no experimental binding site structural information. Here we introduce a methodological enhancement to integrate protein structure information into the model induction process in order to construct more robust physical models. The structure-guided models accurately predict binding affinities over a broad range of compounds while producing more accurate representations of the protein pockets and ligand binding modes. Structure-guidance for the QMOD method yielded significant performance improvements, especially in cases where predictions were made on ligands very different from those used for model induction.