1. Miroslav Brumovský28th July 2011 Miroslav Brumovský 28 th July 2011 Methods using polarization for in silico fragment-based drug design

2. Miroslav Brumovský28th July 2011 2/12 Outline theoretical background goal of the project methods used results

3. Miroslav Brumovský28th July 2011 3/12 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. Miroslav Brumovský28th July 2011 4/12 Molecular docking most popular method for virtual screening predicts the energy and orientation of ligand molecules with a receptor in 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. Miroslav Brumovský28th July 2011 5/12 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. Miroslav Brumovský28th July 2011 6/12 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/MM charges) – ligand atomic charges computed by QM (B3LYP/6-311+G*) with receptor atomic charges (MM) computed by Method of induced charges

7. Miroslav Brumovský28th July 2011 7/12 Model systems 1EQG1FV9 1GWQ1N1M 1QWC 1WCC 1YZ3 2C902OHK 2JJC Congreve, M et al. (2008) J. Med. Chem, 51, 3661-3680. 1 2 5 34 6 7 9 10 11 12 1S39 8 2ADU

8. Miroslav Brumovský28th July 2011 8/12 Results Methods: M1 – standard docking, M2 - docked with QM/MM charges, M3 - docked with MM polarized QM/MM ligand charges RMSD < 2 Å

9. Miroslav Brumovský28th July 2011 9/12 Example – docking of 1N1M A. Standard docking, docking with polarized QM/MM ligand charges B. Docking with polarized both receptor (MM charges) and ligand (QM/MM charges) RMSD = 1.4 Å RMSD = 0.9 Å

10. Miroslav Brumovský28th July 2011 10/12 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. Miroslav Brumovský28th July 2011 11/12 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. Miroslav Brumovský28th July 2011 Thank you for your attention