title: Molecular dynamics in drug design.
abstract: 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.
authors.affiliation: Department of Biochemistry, University of Zurich, CH-8057 Zurich, Switzerland.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Zhao
authors.affiliation: Department of Biochemistry, University of Zurich, CH-8057 Zurich, Switzerland. Electronic address: caflisch@bioc.uzh.ch.
authors.forename: Amedeo
authors.initials: A
authors.lastname: Caflisch
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry*; D057166:High-Throughput Screening Assays; D006801:Humans; D008024:Ligands; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D010447:Peptide Hydrolases / Q000737:chemistry*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000737:chemistry; D054852:Small Molecule Libraries / Q000737:chemistry*; D013329:Structure-Activity Relationship; D014584:User-Computer Interface
chemical_list: D004791:Enzyme Inhibitors; D008024:Ligands; D054852:Small Molecule Libraries; D011505:Protein-Tyrosine Kinases; D010447:Peptide Hydrolases
keywords: Atomistic simulation; Bromodomains; High-throughput docking; In silico screening; Proteases; Tyrosine kinases