Flexible ligand docking to multiple receptor conformations: a practical alternative

Abstract

State of the art docking algorithms predict an incorrect binding pose for about 50-70% of all ligands when only a single fixed receptor conformation is considered. In many more cases, lack of receptor flexibility results in meaningless ligand binding scores, even when the correct pose is obtained. Incorporating conformational rearrangements of the receptor binding pocket into predictions of both ligand binding pose and binding score is crucial for improving structure-based drug design and virtual ligand screening methodologies. However, direct modeling of protein binding site flexibility remains challenging because of the large conformational space that must be sampled, and difficulties remain in constructing a suitably accurate energy function. Here we show that using multiple fixed receptor conformations, either experimentally determined by crystallography or NMR, or computationally generated, is a practical shortcut that may improve docking calculations. In several cases, such an approach has led to experimentally validated predictions.

Figure 1

Multiple receptor conformation (MRC) docking flowchart. The filtering step of the flowchart may be skipped if the number of initial conformations is small. The refinement step is skipped in some implementations of the MRC docking.

Figure 2

A derivative of an antipsychotic drug discovered to have anti-androgenic activity [30]. The antagonist bound androgen receptor models were generated using a ligand-steered pocket generator and an ensemble docking of the benchmark ligands.