Advances in molecular dynamics simulations and free-energy calculations relevant for drug design

Abstract

Future Science Book SeriesIn Silico Drug Discovery and Design Advances in molecular dynamics simulations and free-energy calculations relevant for drug designNadine Homeyer & Holger GohlkeNadine HomeyerNadine Homeyer is a postdoctoral researcher at the Institute for Pharmaceutical and Medicinal Chemistry, Heinrich-Heine University, Düsseldorf, Germany. She obtained her PhD in 2008 from the University Erlangen-Nuremberg, where she studied the influence of phosphorylation on structure, dynamics and interaction of proteins. Currently, she investigates ligand binding and the properties of biomolecular systems by molecular dynamics simulations and free-energy calculations.Search for more papers by this author & Holger GohlkeHolger Gohlke is a Professor of Pharmaceutical and Medicinal Chemistry at the Heinrich-Heine University. His research aims at understanding and predicting receptor–ligand interactions and the modulation of biological processes by pharmacologically relevant molecules. His group develops and applies methods at the interface of computational pharmaceutical and biophysical chemistry and molecular bioinformatics.Search for more papers by this authorPublished Online:21 Oct 2013https://doi.org/10.4155/ebo.12.449AboutSectionsView ArticleView Full TextPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack Citations ShareShare onFacebookTwitterLinkedInReddit View chapterAbstract: Drug compounds and their biomolecular targets are no rigid objects, but exhibit, due to motions on the atomic level, dynamic changes in their structure. Molecular dynamics (MD) simulations describe these motions using the laws of classical mechanics. Simulations considering the dynamics of ligand–target systems provide information that is not accessible from static structures. As such, MD simulations can reveal transiently accessible binding sites, give insights into the process of ligand binding and release, and provide information about dynamic receptor–ligand contacts. Furthermore, MD-based free-energy calculations allow computing binding energies for ranking ligands according to their binding affinity to a biomolecular target. The applications of MD simulations and free-energy calculations in drug design and the types of methods used are manifold. Here, we focus on recent studies and methodological advances that are likely to play a role in future drug design. References1 Durrant JD , McCammon JA . Molecular dynamics simulations and drug discovery . BMC Biol. 9 (71) , 1 – 9 (2011) . Medline, Google Scholar2 Henrich S , Salo-Ahen OMH , Huang B et al. Computational approaches to identifying and characterizing protein binding sites for ligand design . J. Mol. Recognit. 23 (2) , 209 – 219 (2009) . Google Scholar3 Metz A , Pfleger C , Kopitz H et al. Hot spots and transient pockets: predicting the determinants of small-molecule binding to a protein–protein interface . J. Chem. Inf. Model. 52 (1) , 120 – 133 (2012) . 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Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByBiasing Potential Replica Exchange Multisite λ-Dynamics for Efficient Free Energy Calculations17 February 2015 | Journal of Chemical Theory and Computation, Vol. 11, No. 3Rapid Alchemical Free Energy Calculation Employing a Generalized Born Implicit Solvent Model11 September 2014 | The Journal of Physical Chemistry B, Vol. 119, No. 3Practical Aspects of Free-Energy Calculations: A Review6 June 2014 | Journal of Chemical Theory and Computation, Vol. 10, No. 7 In Silico Drug Discovery and DesignMetrics Downloaded 44 times History Published online 21 October 2013 Published in print October 2013 Information© Future Science Ltd© Future Science LtdPDF download