Accelerating Lead Optimization Away from Anti-Targets: Navigating the Structural Complexity of Promiscuous ADMET Proteins

Abstract The development of a small molecule suitable for clinical use involves optimization of ligand binding to an identified target protein but also frequently the reduction of binding to a variety of anti-target proteins known to pose translational risk. These anti-targets, often referred to as ADMET proteins, often contain large, highly flexible binding sites, leading to promiscuous binding of small molecules. This property often frustrates efforts to execute structure-based design against these anti-targets. Here, we demonstrate the application of a combination of induced fit docking and free energy perturbation to structurally enable several of the most common anti-targets: cytochrome P450 isoforms 3A4 and 2D6, the hERG ion channel, and PXR. Crucially, the enforcement of a consensus binding mode across a congeneric series allowed for the efficient exploration of a wide range of receptor conformational space. Results are presented for both public retrospective datasets and prospective application in active drug discovery programs.