Biased Docking for Protein–Ligand Pose Prediction

ARCON, JUAN PABLO; TURJANSKI, ADRIÁN G.; MARTÍ, MARCELO A.; FORLI, STEFANO

METHODS IN MOLECULAR BIOLOGY (CLIFTON, N.J.)

Humana Press Inc.

Año: 2021 vol. 2266 p. 39 - 72

1064-3745

The interaction between a protein and its ligands is one of the basic and most important processes in biological chemistry. Docking methods aim to predict the molecular 3D structure of protein–ligand complexes starting from coordinates of the protein and the ligand separately. They are widely used in both industry and academia, especially in the context of drug development projects. AutoDock4 is one of the most popular docking tools and, as for any docking method, its performance is highly system dependent. Knowledge about specific protein–ligand interactions on a particular target can be used to successfully overcome this limitation. Here, we describe how to apply the AutoDock Bias protocol, a simple and elegant strategy that allows users to incorporate target-specific information through a modified scoring function that biases the ligand structure towards those poses (or conformations) that establish selected interactions. We discuss two examples using different bias sources. In the first, we show how to steer dockings towards interactions derived from crystal structures of the receptor with different ligands; in the second example, we define and apply hydrophobic biases derived from Molecular Dynamics simulations in mixed solvents. Finally, we discuss general concepts of biased docking, its performance in pose prediction, and virtual screening campaigns as well as other potential applications.