Efficient inclusion of receptor flexibility in grid‐based protein–ligand docking*

Accounting for receptor flexibility is an essential component of successful protein–ligand docking but still marks a major computational challenge. For many target molecules of pharmaceutical relevance, global backbone conformational changes are relevant during the ligand binding process. However, popular methods that represent the protein receptor molecule as a potential grid typically assume a rigid receptor structure during ligand–receptor docking. A new approach has been developed that combines inclusion of global receptor flexibility with the efficient potential grid representation of the receptor molecule. This is achieved using interpolation between grid representations of the receptor protein deformed in selected collective degrees of freedom. The method was tested on the docking of three ligands to apo protein kinase A (PKA), an enzyme that undergoes global structural changes upon inhibitor binding. Structural variants of PKA were generated along the softest normal mode of an elastic network representation of apo PKA. Inclusion of receptor deformability during docking resulted in a significantly improved docking performance compared with rigid PKA docking, thus allowing for systematic virtual screening applications at small additional computational cost. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011