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Miroslav Brumovský

28 th July 2011. Miroslav Brumovský. Methods using polarization for in silico fragment-based drug design. Outline. theoretical background goal of the project methods used results. Drug design. inventive process of finding new medications

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Miroslav Brumovský

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  1. 28th July 2011 Miroslav Brumovský Methods using polarization for insilico fragment-based drug design

  2. Outline • theoretical background • goal of the project • methods used • results

  3. Drug design • inventive process of finding new medications • key process is screening libraries of potential drug compounds (in vivo essays x virtual screening) • this can be done using two approaches • screening of huge libraries of complete compounds • screening of drug fragments → fragment-based drug design • fragment-based drug design benefits from better sensitivity and limited need of screened molecules than the classical approach

  4. Molecular docking • most popular method for virtual screening • predicts the energy and orientation of ligand moleculeswith a receptorin a stable complex (“lock-and-key” problem) • algorithms treating flexible ligand and rigid receptor → best results • results are sorted by scoring function (relative energy) • scoring function usually calculated using force-field atomic charges (no polarization) • when used in FBDD, more accurate (polarized) atomic charges for energy calculations are needed

  5. Goal of the project • improvement of standard molecular docking for more accurate prediction of the ligand-receptor interaction using methods based on polarization • development of a new method applicable in computer-assisted drug design

  6. Methods • standard molecular docking (Glide) • standard atomic charges assigned from force-field • docking with polarized QM/MM ligand charges • ligand atomic charges computed by QM calculations with standard receptor charges (B3LYP/6-311+G*) • docking with polarized both receptor (MM charges) and ligand (QM/MMcharges) • ligand atomic charges computed by QM (B3LYP/6-311+G*) with receptor atomic charges (MM) computed by Method of induced charges

  7. Model systems 1 3 4 2 1GWQ 1N1M 1EQG 1FV9 5 7 8 6 1WCC 2ADU 1YZ3 1QWC 9 11 10 12 2JJC 1S39 2C90 2OHK Congreve, M et al. (2008)J. Med. Chem, 51, 3661-3680.

  8. Results RMSD < 2 Å Methods: M1 – standard docking, M2 - docked with QM/MM charges, M3 - docked with MM polarized QM/MM ligand charges

  9. Example – docking of 1N1M RMSD = 0.9 Å RMSD = 1.4 Å A. Standard docking, docking with polarized QM/MM ligand charges B. Docking with polarized both receptor (MM charges) and ligand (QM/MMcharges)

  10. Conclusions • improved methods for docking are more accurate • effect of receptor polarization is not so relevant comparing to the calculations with lower QM basis set • this advanced approach can be succesfully used in fragment-based drug design

  11. Acknowledgement I would like to say thanks to… my supervisor, Dr. David Řeha, for very educational and friendly leading, University of Essex for providing computational software, organizers of Schola Ludus for the opportunity to participate on the project.

  12. Thank you for your attention

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