2. X-rays Wilhelm Roentgen

3. Penicillin Alexander Fleming Howard Florey Ernst Chain

7. Review and re-review

9. Industrial Drug Development High throughput screening Long and elaborate Hit-to-Lead process Confidential and Proprietary

11. Shoot another 500 rockets to get one to Mars.

13. Confidential and Proprietary Crystallography -> Design -> Synthesis -> Evaluation -> Crystallography -> …

14. Why can’t theory help? The underlying physical laws necessary for the mathematical theory of a large part of physics and the whole of chemistry are thus completely known, and the difficulty is only that the exact application of these laws leads to equations much too complicated to be soluble. P. A. M. Dirac, Proc. R. Soc. London 123, 714 (1929) This is no longer true, computers can solve the equations. Given 10^12 years. Confidential and Proprietary

15. Current force-fields are too simple Confidential and Proprietary

17. Parameters change with different applications: a sign of an incomplete model

18. Polarizability fundamentally impossible Confidential and Proprietary

19. Polarization is crucial in drug design Confidential and Proprietary

20. QUANTUM MECHANICAL POLARIZABLEFORCE FIELD (QMPFF) All major current force fields including AMBER and Merck Molecular Force Field (MMFF) are based on similar principles that date back decades ago QMPFF is designed to be physically more realistic and therefore more accurate by fully integrating quantum physics – made possible by vast increases in computer speed to do necessary calculations

21. +1 +1 QMPFF CONCEPT Conventional Molecular Representation QMPFF Molecular Representation H2O H2O + 0.4 - 0.45 - 7.1 +6 - 0.8 - 0.45 + 0.4 Point charges known to be physically unrealistic; no natural way to include important polarization energy term Charge clouds approximate quantum reality; polarization naturally introduced via shifting of electron clouds

22. QMPFF technology captures the missing details Quantum Mechanical Polarizable Force Field (QMPFF) Polarizable force field models polar interactions (see below) Can model water, gas phase, ligand binding better than any existing computational tools using the same parameters. Produced Dipole Electric Field + Confidential and Proprietary

23. Interacting entities are cloud-like, polarizable O Parameterized from QM calculations. Polarizability is essential to modeling biological interactions. Electron clouds adjust during the simulation-> (real VdW). + - - - + + H H Confidential and Proprietary

24. WATER SIMULATIONS WITH QMPFF2

25. QMPFF vs MMFF94 RING-STACKING OF BENZENE DIMER

26. QMPFF AND DRUG DESIGN QMPFF via MD simulation can be applied to calculate relative binding free energy (and therefore relative binding affinity) of two related ligands for a protein X-ray structure of protein is required, and structure of complex with representative ligand(s) is very helpful

27. We mutate one ligand into another Thermodynamic integration Each alchemical mutation requires running a series of simulations. Takes approximately 8 days per calculation (10 cores). Most suitable for lead and drug optimization. Mutation Confidential and Proprietary

28. 2BZA benzyl-ammonium BINDING FREE ENERGY CALCULATIONS FOR 1TNH AND 2BZA IN TRYPSIN 1TNH 4-fluoro-benzyl-ammonium ΔΔG (kcal/mol) QMPFF3 0.85  0.17 MMFF94 -0.4 Exper. 0.78

29. Does it work? Ligand substitution pilot study (trypsin, thrombin and uPA inhibitor families). Nothing else can predict free energies accurately (see comparison to Merck results below) QMPFF MMFF Confidential and Proprietary Actual

30. Does it work?

31. Does it work? Drug design – blind prediction ---------Predicted Measured Reference compound L

32. Speed-accuracy tradeoffthe exception Confidential and Proprietary Speed 10^12 years 1 week 0.01 sec QM QMPFF Necessary accuracy Precision Conventional Force Fields Docking (Snapshot)

34. Difficult synthesis can be virtual

35. Scaling with available computers