Molecular dynamics in drug design

• Mapping hot spots of proteins.
• Thermodynamics and kinetics of small molecules binding to proteins.
• Generation of protein conformation ensembles for in silico drug design.
• Validation of binding modes predicted by docking.
• Elucidation of mechanism of action of drugs and natural ligands.

Molecular dynamics (MD) simulations are useful tools for structure-based drug design. We review recent publications in which explicit solvent MD was used at the initial or final stages of high-throughput docking campaigns. In some cases, MD simulations of the protein target have been carried out before docking to generate a conformer of the protein which differs from the available crystal structure(s). Furthermore, MD runs have been performed after docking to assess the predicted binding modes of the top ranking compounds as final filter in silico or to guide chemical synthesis for hit optimization. We present examples of in silico discoveries of tyrosine kinase inhibitors and bromodomain antagonists whose binding mode was predicted by automated docking and further corroborated by MD simulations with final validation by X-ray crystallography.

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