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EUGM 2013 - Odon Farkas (Eotvos University) - Conformation search via cool dynamics
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EUGM 2013 - Odon Farkas (Eotvos University) - Conformation search via cool dynamics

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The present method is the basis of the developing Conformation Plugin, a new calculator tool in Marvin. Our method is not one of the usual conformer search techniques, as it uses a new molecular ...

The present method is the basis of the developing Conformation Plugin, a new calculator tool in Marvin. Our method is not one of the usual conformer search techniques, as it uses a new molecular dynamics method to directly provide ready-to-use low energy conformations. The advantage of conformation search instead of optimizing conformers, when one is looking for bioactive conformations, is shown. We present the highlights of the algorithm and comparisons based on data published recently.

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EUGM 2013 - Odon Farkas (Eotvos University) - Conformation search via cool dynamics EUGM 2013 - Odon Farkas (Eotvos University) - Conformation search via cool dynamics Presentation Transcript

  • Conformation Search viaCool DynamicsÖdön Farkas
  • Comparison ofRegular vs. Cool Dynamics
  • Comparison of Regular vs.Cool DynamicsComparison ofRegular vs. Cool Dynamics
  • Comparision of Regular vs.Cool DynamicsComparison ofRegular vs. Cool Dynamics
  • Comparison of Regular vs.Cool DynamicsThe distorted structures in regular dynamics, lead to large difference in potential energies:Regular: 578 kcal/mol Cool: 35 kcal/mol
  • Arguments against constrained dynamics0 50 100 150 200 250 300 350 400-100102030405060Relative potential energy curve for relaxed and rigid phenyl rotationin the case of LorazepamRigidRelaxedRotation / degreeRelativeenergykcal/mol
  • Arguments against constrained dynamics0 50 100 150 200 250 300 350 400-100102030405060Relative potential energy curve for relaxed and rigid phenyl rotationin the case of LorazepamRigidRelaxedRotation / degreeRelativeenergykcal/molConstraints in molecular dynamics change the potential energy surface
  • Applying new Conformation Plugin to findconformers of LorazepamThe expected 2 conformers found (left column).The additional 4 conformers are due to the flexibility of the 7 member ring, also found
  • • Internal coordinate projections3‐ The dynamics simulation remains in Cartesian coordinates‐ Projection of the momentum‐ Avoid redundancy via natural internals1‐ Fast transformations3,7• Sparse Cholesky decomposition4,5,7Science used in cool dynamics
  • • Novel tools in the new plugin‐ Conformation selection uses generalizedStructure Stream interface‐ Topology-aware selection‐ Optional optimization7 for conformer search‐ MMFF94 forcefield2‐ Cool dynamics is the default stream sourceNew Conformation Plugin
  • 0 0.5 1 1.5 2 2.5 3 3.5 400.511.522.533.54Conformation Plugin vs. RDKit RMSDRDKit RMSDConformationPluginRMSDComparison of New Conformation Plugin toRDKit in finding bioactive conformation
  • In situ structure-based design on the web
  • AcknowledgmentsChemAxons Discovery TeamTimea PolgárGábor ImreFilip SedlakAdrián KalásziMiklós J. Szabó
  • Thank you for your attention!
  • References1. G. Fogarasi, X. Zhou, P. W. Taylor, and P. Pulay, J. Am. Chem. Soc., 1992, 114, 81912. Thomas A. Halgren Merck molecular force field. I. Basis, form, scope, parameterization, and performance ofMMFF94, J. Comp. Chem.; 1996; 490-5193. Farkas, Ö.; Schlegel, H. B.; Methods for optimizing large molecules. I An O(N2) algorithm for solving systemsof linear equations for coordinate transformations in quantum chemical geometry optimization. J. Chem.Phys. 1998, 109, 7100-4.4. B. Paizs, G. Fogarasi, and P. Pulay An efficient direct method for geometry optimization of large molecules ininternal coordinates J. Chem. Phys. 1998, 109, 6571;5. B. Paizs, J. Baker, S. Suhai and P. Pulay, Geometry Optimization of Large Biomolecules in Redundant InternalCoordinates, J. Chem. Phys. 2000 113(16), 6566.6. P. Pulay and B. Paizs, Newtonian Molecular Dynamics In General Curvilinear Internal Coordinates, Chem.Phys. Lett., 2002, 353, 400.7. Farkas, Ö.; Schlegel, H. B. Geometry optimization methods for modeling large molecules, Journal ofMolecular Structure-Theochem 2003, 666, 31-39.8. Jean-Paul Ebejer, Garrett M. Morris, and Charlotte M. Deane Freely Available Conformer GenerationMethods: How Good Are They? J. Chem. Inf. Model., 2012, 52 (5), 1146–1158