The importance of basic science<br /><ul><li> Major advances in medicine from apparently unrelated discoveries:</li></ul>X...
X-rays<br />Wilhelm Roentgen<br />
Penicillin<br />Alexander Fleming<br />Howard Florey<br />Ernst Chain<br />
The importance of basic science<br /><ul><li> Major advances in medicine from apparently unrelated discoveries:</li></ul>X...
 Solve problems indirectly</li></li></ul><li>Support for discovery<br />Do not:<br /><ul><li> Define specific areas or pri...
 Judge proposals on details</li></ul>Do:<br /><ul><li> Fund individual investigators, directly, based on merits of proposals
 Review and re-review
 Play the odds - the law of large numbers</li></li></ul><li>Confidential and Proprietary<br />Drug design:  Designing a li...
Industrial Drug Development<br />High throughput screening<br />Long and elaborate Hit-to-Lead process<br />Confidential a...
Confidential and Proprietary<br />If we did a space launch the way we design drugs we would:<br /><ul><li>Shoot 100 rocket...
Shoot another 500 rockets to get one to Mars.
Each new satellite would have to be very similar to a previous one. </li></li></ul><li>This is one of the reasons for Phar...
Confidential and Proprietary<br />Crystallography -> Design ->  Synthesis -> Evaluation -> Crystallography -> …<br />
Why can’t theory help?<br />The underlying physical laws necessary for the mathematical theory of a large part of physics ...
Current force-fields are too simple<br />Confidential and Proprietary<br />
Current force-fields are parametrized depending on application: not extensible<br /><ul><li>Do not respond to environment
Parameters change with different applications: a sign of an incomplete model
Polarizability fundamentally impossible  </li></ul>Confidential and Proprietary<br />
Polarization is crucial in drug design<br />Confidential and Proprietary<br />
QUANTUM MECHANICAL POLARIZABLEFORCE FIELD (QMPFF)<br />All major current force fields including AMBER and Merck Molecular ...
+1<br />+1<br />QMPFF CONCEPT<br />Conventional Molecular <br />Representation <br />QMPFF Molecular <br />Representation ...
QMPFF technology captures the missing details<br />Quantum Mechanical Polarizable Force Field (QMPFF)<br />Polarizable for...
Interacting entities are cloud-like, polarizable<br />O<br />Parameterized from QM calculations. <br />Polarizability is e...
WATER SIMULATIONS WITH QMPFF2<br />
QMPFF vs MMFF94 RING-STACKING OF BENZENE DIMER<br />
QMPFF AND DRUG DESIGN<br />QMPFF via MD simulation can be applied to calculate relative binding free energy (and therefore...
We mutate one ligand into another<br />Thermodynamic integration<br />Each alchemical mutation requires running a series o...
2BZA<br />benzyl-ammonium<br />BINDING FREE ENERGY CALCULATIONS FOR 1TNH AND 2BZA IN TRYPSIN<br />1TNH<br />4-fluoro-benzy...
Does it work?<br />Ligand substitution pilot study (trypsin, thrombin and uPA inhibitor families). <br />Nothing else can ...
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Roger kornberg the importance of basic science

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Roger kornberg the importance of basic science

  1. 1. The importance of basic science<br /><ul><li> Major advances in medicine from apparently unrelated discoveries:</li></ul>X-rays, antibiotics, nonivasive imaging, genetic<br />engineering<br />
  2. 2. X-rays<br />Wilhelm Roentgen<br />
  3. 3. Penicillin<br />Alexander Fleming<br />Howard Florey<br />Ernst Chain<br />
  4. 4. The importance of basic science<br /><ul><li> Major advances in medicine from apparently unrelated discoveries:</li></ul>X-rays, antibiotics, nonivasive imaging, genetic<br />engineering<br /><ul><li> The pursuit of knowledge for its own sake
  5. 5. Solve problems indirectly</li></li></ul><li>Support for discovery<br />Do not:<br /><ul><li> Define specific areas or priorities – let the best ideas win
  6. 6. Judge proposals on details</li></ul>Do:<br /><ul><li> Fund individual investigators, directly, based on merits of proposals
  7. 7. Review and re-review
  8. 8. Play the odds - the law of large numbers</li></li></ul><li>Confidential and Proprietary<br />Drug design: Designing a ligand to fit into a protein and interfere with function<br />Henry Moore, Two Forms<br />Pynkado wood, 1934<br />Metropolitan Museum of Art, New York<br />© MMA, N.Y. <br />
  9. 9. Industrial Drug Development<br />High throughput screening<br />Long and elaborate Hit-to-Lead process<br />Confidential and Proprietary<br />
  10. 10. Confidential and Proprietary<br />If we did a space launch the way we design drugs we would:<br /><ul><li>Shoot 100 rockets to the Moon in hope of landing one.
  11. 11. Shoot another 500 rockets to get one to Mars.
  12. 12. Each new satellite would have to be very similar to a previous one. </li></li></ul><li>This is one of the reasons for Pharmaceutical industry’s troubles.<br />Confidential and Proprietary<br />Money spent on R&D<br />Approved Drugs<br />T.T. Ashburn and K.B. Thor, Nature Rev. Drug Discov. 3, 673-683 (2004)<br />
  13. 13. Confidential and Proprietary<br />Crystallography -> Design -> Synthesis -> Evaluation -> Crystallography -> …<br />
  14. 14. Why can’t theory help?<br />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.<br />P. A. M. Dirac, Proc. R. Soc. London 123, 714 (1929)<br />This is no longer true, computers can solve the equations. Given 10^12 years. <br />Confidential and Proprietary<br />
  15. 15. Current force-fields are too simple<br />Confidential and Proprietary<br />
  16. 16. Current force-fields are parametrized depending on application: not extensible<br /><ul><li>Do not respond to environment
  17. 17. Parameters change with different applications: a sign of an incomplete model
  18. 18. Polarizability fundamentally impossible </li></ul>Confidential and Proprietary<br />
  19. 19. Polarization is crucial in drug design<br />Confidential and Proprietary<br />
  20. 20. QUANTUM MECHANICAL POLARIZABLEFORCE FIELD (QMPFF)<br />All major current force fields including AMBER and Merck Molecular Force Field (MMFF) are based on similar principles that date back decades ago<br />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<br />
  21. 21. +1<br />+1<br />QMPFF CONCEPT<br />Conventional Molecular <br />Representation <br />QMPFF Molecular <br />Representation <br />H2O<br />H2O<br />+ 0.4<br />- 0.45<br />- 7.1<br />+6<br />- 0.8<br />- 0.45<br />+ 0.4<br />Point charges known to be physically unrealistic; no natural way to include important polarization energy term<br />Charge clouds approximate quantum reality; polarization naturally introduced via shifting of electron clouds<br />
  22. 22. QMPFF technology captures the missing details<br />Quantum Mechanical Polarizable Force Field (QMPFF)<br />Polarizable force field models polar interactions (see below)<br />Can model water, gas phase, ligand binding better than any existing computational tools using the same parameters. <br />Produced Dipole<br />Electric Field<br />+<br />Confidential and Proprietary<br />
  23. 23. Interacting entities are cloud-like, polarizable<br />O<br />Parameterized from QM calculations. <br />Polarizability is essential to modeling biological interactions. <br />Electron clouds adjust during the simulation-> (real VdW).<br />+<br />-<br />-<br />-<br />+<br />+<br />H<br />H<br />Confidential and Proprietary<br />
  24. 24. WATER SIMULATIONS WITH QMPFF2<br />
  25. 25. QMPFF vs MMFF94 RING-STACKING OF BENZENE DIMER<br />
  26. 26. QMPFF AND DRUG DESIGN<br />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<br />X-ray structure of protein is required, and structure of complex with representative ligand(s) is very helpful<br />
  27. 27. We mutate one ligand into another<br />Thermodynamic integration<br />Each alchemical mutation requires running a series of simulations. <br />Takes approximately 8 days per calculation (10 cores). <br />Most suitable for lead and drug optimization. <br />Mutation<br />Confidential and Proprietary<br />
  28. 28. 2BZA<br />benzyl-ammonium<br />BINDING FREE ENERGY CALCULATIONS FOR 1TNH AND 2BZA IN TRYPSIN<br />1TNH<br />4-fluoro-benzyl-ammonium<br />ΔΔG (kcal/mol)<br />QMPFF3 0.85  0.17<br />MMFF94 -0.4 <br />Exper. 0.78<br />
  29. 29. Does it work?<br />Ligand substitution pilot study (trypsin, thrombin and uPA inhibitor families). <br />Nothing else can predict free energies accurately (see comparison to Merck results below)<br />QMPFF<br />MMFF<br />Confidential and Proprietary<br />Actual<br />
  30. 30. Does it work?<br />
  31. 31. Does it work?<br />Drug design – blind prediction<br />---------Predicted<br />Measured<br />Reference <br />compound<br />L<br />
  32. 32. Speed-accuracy tradeoffthe exception<br />Confidential and Proprietary<br />Speed<br />10^12 years<br />1 week<br />0.01 sec<br />QM<br />QMPFF<br />Necessary <br />accuracy<br />Precision<br />Conventional <br />Force Fields<br />Docking<br />(Snapshot)<br />
  33. 33. Impact on drug design<br />Confidential and Proprietary<br /><ul><li>Speeding up binding optimization
  34. 34. Difficult synthesis can be virtual
  35. 35. Scaling with available computers
  36. 36. Making best of class drugs </li></li></ul><li>SOME APPLICATIONS OF QMPFF<br />Hydrogen storage and fuel cells<br />Batteries<br />Optical materials<br />Catalysts<br />
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