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Application of MM-PBSA Free Energy Methods in Drug Discovery |
InterAction Meeting Session, Bryn Mawr, Philadelphia, USA
Tuesday 14 October 2008
chaired by Judith Lalonde (Bryn Mawr College) Bio....
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The successful use of computational methods to enhance the drug discovery process relies on the ability to adequately predict binding affinity of compounds prior to synthesis. Over the past several years several studies have pointed to the limitations in using empirical or molecular mechanics based scoring functions to predict relative potencies of congeneric series of compounds. A number of approximate free-energy based computational methods have been developed to more closely predict ligand binding affinities. The Molecular Mechanics-Poisson-Boltzmann Surface Area (MM-PBSA) is one approximate method that is being successfully applied in structure-based drug discovery. Variations to the MM-PBSA methodology include explicit or implicit solvent and choice of solvation model, Poisson Boltzmann (PB) or Generalized Born (GB). This session will address various uses of the MM-PBSA/MM-GBSA methods in evaluating protein-ligand interactions.
The first portion of the session focuses first on the fundamentals and applications of implicit solvent models. Details of the Generalized Born (GB) implicit solvent model as applied to MM-GBSA will be discussed by Dr. Alexey Onufriev. Dr. David Case will describe uses of MM-GBSA in rescoring docked ligands. Dr. Rommie Amaro will compare and contrast the use of explicit and implicit solvent models in molecular dynamics simulations of Influenza Neuraminidases. Dr. Peter Coveney will demonstrate the use of MM-PBSA method to HIV protease as implemented over a highly distributed computational infrastructure. Dr. Anna Kohlmann will elaborate on the use of MM-GBSA in post scoring of kinase inhibitors and its use in developing local models. Dr. Scott Brown will close the session by presenting an analysis of MM-PBSA performance across several protein targets.
Presenters & Discussions Leaders
Rommie Amaro (USCD), Comparative Studies using Explicit and Generalized Born Molecular Dynamics Simulations of Influenza Neuraminidases Abstract & Bio....
Scott Brown (Abbott), In what Contexts can we reliably use MM-PBSA in Industrial Drug Discovery Abstract & Bio....
David Case (Rutgers University), Scoring and Re-scoring Ligand Binding Energies using Implicit Solvent Models Abstract & Bio....
Peter Coveney (Univ. College London), Rapid and Accurate Determination of Binding Free Energies in Protein-Drug Systems using Automated Workflows across Federated Intercontinental Supercomputing Grids Abstract & Bio....
Anna Kohlmann (Ariad Pharmaceuticals), Deploying Prime MM-GBSA in Kinase Inhibitor Lead Optimization: from Docking to Local QSAR models Abstract & Bio....
Alexey Ornufriev (Virginia Tech), Implicit Solvent models: Practical Uses, Advantages and Limitations Abstract & Bio....
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