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Introduction to computational chemistry. Ivan Stambolic University of Regensburg Group of Prof. Dr Bernhard Dick Kostenz , 26. 03. 2014 . Biology (in one slide!). Transcription Translation.
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Introduction to computational chemistry Ivan Stambolic University of Regensburg Group of Prof. Dr Bernhard Dick Kostenz, 26. 03. 2014.
Biology (in one slide!) Transcription Translation DNA RNA Protein (genomics) Central dogma (proteomics)
Computational chemistry • Computational chemistry is a branch of chemistry that uses computer simulation to assist in solving chemical problems • Theoretical chemistry methods • Efficient computer programs
Purpose and use of comp. chem. • Predict molecular properties • Predict reactants, intermediates and reaction products • QSAR and QSPR • Designing molecules with specific properties and interactions • Chemical databases
Real world examples Flu cure • Zanamivir(Relenza®) by GlaxoSmithKline • Treatment of flu caused by Influenza A and B viruses • One of the first drugs to be developed using Molecular Modelling • Neuraminidase inhibitor
Zanamivir Neuraminidase with Sialic acid in it’s active site
Real world examplesNew class of antibiotics • Methicillin-resistant Staphylococcus aureus (MRSA) • Public health problem since 1960s • Estimated 20,000 deaths per year in USA alone • 64% of all MRSA infections are hospital-acquired (HA-MRSA) • Only 3 drugs currently exist for treating MRSA • Resistance to each of those drugs already exists M. Chang et al, JACS, 2014, 136 (9), pp 3664–3672, DOI: 10.1021/ja500053x
Real world examplesNew class of antibiotics • First antibiotic group after 30 years to be discovered • Oxadiazole inhibits • a penicillin-binding protein, PBP2a • the biosynthesis of the cell wall that enables MRSA to resist other drugs • Oxadiazole discovered In silico,using virtual screening technique
Comp. chem. classification • Molecular modelling • Empirical methods • Semi-empirical methods • Ab initio methods • Chemoinformatics • Chemical databases • Systematization, analysis and discovery of regularities in vast amount of data • Predictions based on found regularities
Chemoinformatics • Database of Interacting Proteins (http://dip.doe-mbi.ucla.edu) GTP-Rac1 interactions
Protein structure prediction • Protein structure prediction is the prediction of the three-dimensional structure of a protein from its amino acid sequence • Modelling • Comparative modelling • De novo modelling
Docking • Docking predicts the preferred orientation of one molecule to a second, when bound to each other to form a stable complex • Starts from their unbound structures • Used in Virtual screening
Molecular dynamics simulations • Molecular dynamics (MD) is a computer simulation of physical movements of atoms and molecules • The atoms and molecules are allowed to interact for a period of time, giving a view of the motion of the atoms
Molecular dynamics simulations The Nobel Prize in Chemistry 2013 was awarded jointly to Martin Karplus, Michael Levitt and AriehWarshel"for the development of multiscale models for complex chemical systems“ http://www.nobelprize.org/nobel_prizes/chemistry/laureates/2013/
Overview: Computation chemistry • Theoretical methods incorporated in efficient computer programs • Modelling – predict tertiary and quaternary structures of proteins • Docking – predict preferred binding pose of two non-covalently bound molecules • MD – simulate movement and interactions of molecules in time
Statistics H. Sies, Nature (1988) 332:495
Acknowledgments • Prof. Dr Bernhard Dick • PD Dr Stephan Baeurle • Kathrin Magerl • DrEmanuel Peter • SergeiiDonets • Dr Anton Pershin • GRK 1626 Chemical Photocatalysis
