title: Rapid estimation of relative protein-ligand binding affinities using a high-throughput version of MM-PBSA.
abstract: By employing a modified protocol of the Molecular Mechanics with Poisson-Boltzmann Surface Area (MM-PBSA) methodology we substantially decrease the required computation time for calculating relative estimates of protein-ligand binding affinities. The modified method uses a generalized Born implicit solvation model during molecular dynamics to enhance conformational sampling as well as a very efficient Poisson-Boltzmann solver and a computational design based on a distributed-computing paradigm. This construction allows for reduction of the computational cost of the calculations by roughly 2 orders of magnitude compared to the traditional formulation of MM-PBSA. With this high-throughput version of MM-PBSA we show that one can produce efficient physics-based estimates of relative binding free energies with reasonable correlation to experimental data and a total computation time that is sufficiently low such that an industrially relevant throughput can be realized given currently accessible computing resources. We demonstrate this approach by performing a comparison of different MM-PBSA implementations on a set of 18 ligands for the protein target urokinase.
authors.affiliation: Abbott Laboratories, Global Pharmaceutical Research and Development, 100 Abbott Park Road, Abbott Park, Illinois 60064-6115, USA. scott.brown@abbott.com
authors.forename: Scott P
authors.initials: SP
authors.lastname: Brown
authors.forename: Steven W
authors.initials: SW
authors.lastname: Muchmore
mesh_terms: D015195:Drug Design; D008024:Ligands; D008958:Models, Molecular; D011485:Protein Binding; D011506:Proteins / Q000378:metabolism*
chemical_list: D008024:Ligands; D011506:Proteins