Physical Chemistry Seminar: Professor Richard Friesner, Columbia University, Sapp Center Lecture Hall, 4:30pm (Host: Tom Markland)
About the Seminar:
"Computational Modeling of Protein-Ligand Binding in the Context of Structure Based Drug Discovery "
We will discuss the use of a range of physics based simulation methods to calculation structures and binding affinities of protein-ligand complexes. Over the past decade, advances in simulation algorithms, molecular mechanics force fields, and computational hardware have enabled binding affinity predictions with an accuracy of better than 1 kcal/mole to be obtained using free energy perturbation (FEP) methods. The methodological advances will be briefly reviewed, followed by a discussion of validation across a wide range of examples. In addition to binding affinity, properties such as ligand solubility, selectivity, and resistance to mutation can be computed effectively. A key point is that relatively large, complex alchemical alterations of the reference molecule can now be handled straightforwardly; perturbations up to 10 heavy atoms, modifications of central ring structures, and changes in the net charge of the ligand are all amenable to FEP simulation. The calculations are efficient enough to enable rapid screening of tens of thousands of “design ideas” and can thus be used to drive lead optimization in the context of structure based drug discovery projects. Examples of this type of application will be presented. Finally, we will discuss the ongoing development of faster, approximate technologies, such as induced fit docking, and empirical scoring functions based on the active site water structure, which when integrated with FEP can significantly increase its domain of applicability as well as the ability to obtain a physical picture of how protein, ligand, and solvent interactions control binding affinity.
About the Speaker:
Richard A. Friesner is Professor of Chemistry at Columbia University and Director of the Columbia Center for Biomolecular Simulation. He is a member of the National Academy of Sciences and American Academy of Arts of Sciences, and has been awarded a Sloan Foundation Fellowship, Camille and Henry Dreyfus Teacher-Scholar Award, and an NIH Research Career Development Award. Current interests include quantum chemistry, development of potential functions for molecular simulation, continuum electrostatic models, and protein folding. Dr. Friesner is a co-founder of Schrödinger, and a member of Schrödinger's Board of Directors.