Application of Drug-Perturbed Essential Dynamics/Molecular Dynamics (ED/MD) to Virtual Screening and Rational Drug Design.

We present here the first application of a new algorithm, essential dynamics/molecular dynamics (ED/MD), to the field of small molecule docking. The method uses a previously existing molecular dynamics (MD) ensemble of a protein or protein-drug complex to generate, with a very small computational cost, perturbed ensembles which represent ligand-induced binding site flexibility in a more accurate way than the original trajectory. The use of these perturbed ensembles in a standard docking program leads to superior performance than the same docking procedure using the crystal structure or ensembles obtained from conventional MD simulations as templates. The simplicity and accuracy of the method opens up the possibility of introducing protein flexibility in high-throughput docking experiments.