title: GeauxDock: A novel approach for mixed-resolution ligand docking using a descriptor-based force field.
abstract: Molecular docking is an important component of computer-aided drug discovery. In this communication, we describe GeauxDock, a new docking approach that builds on the ideas of ligand homology modeling. GeauxDock features a descriptor-based scoring function integrating evolutionary constraints with physics-based energy terms, a mixed-resolution molecular representation of protein-ligand complexes, and an efficient Monte Carlo sampling protocol. To drive docking simulations toward experimental conformations, the scoring function was carefully optimized to produce a correlation between the total pseudoenergy and the native-likeness of binding poses. Indeed, benchmarking calculations demonstrate that GeauxDock has a strong capacity to identify near-native conformations across docking trajectories with the area under receiver operating characteristics of 0.85. By excluding closely related templates, we show that GeauxDock maintains its accuracy at lower levels of homology through the increased contribution from physics-based energy terms compensating for weak evolutionary constraints. GeauxDock is available at http://www.institute.loni.org/lasigma/package/dock/.
authors.affiliation: Department of Physics and Astronomy, Louisiana State University, Baton Rouge, Louisiana, 70803.
authors.forename: Yun
authors.initials: Y
authors.lastname: Ding
authors.affiliation: School of Electrical Engineering and Computer Science, Louisiana State University, Baton Rouge, Louisiana, 70803.|Center for Computation & Technology, Louisiana State University, Baton Rouge, Louisiana, 70803.
authors.forename: Ye
authors.initials: Y
authors.lastname: Fang
authors.affiliation: Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana, 70803.
authors.forename: Wei P
authors.initials: WP
authors.lastname: Feinstein
authors.affiliation: School of Electrical Engineering and Computer Science, Louisiana State University, Baton Rouge, Louisiana, 70803.|Center for Computation & Technology, Louisiana State University, Baton Rouge, Louisiana, 70803.
authors.forename: Jagannathan
authors.initials: J
authors.lastname: Ramanujam
authors.affiliation: School of Electrical Engineering and Computer Science, Louisiana State University, Baton Rouge, Louisiana, 70803.
authors.forename: David M
authors.initials: DM
authors.lastname: Koppelman
authors.affiliation: Department of Physics and Astronomy, Louisiana State University, Baton Rouge, Louisiana, 70803.|Center for Computation & Technology, Louisiana State University, Baton Rouge, Louisiana, 70803.
authors.forename: Juana
authors.initials: J
authors.lastname: Moreno
authors.affiliation: Center for Computation & Technology, Louisiana State University, Baton Rouge, Louisiana, 70803.|Department of Biological Sciences, Louisiana State University, Baton Rouge, Louisiana, 70803.
authors.forename: Michal
authors.initials: M
authors.lastname: Brylinski
authors.affiliation: Department of Physics and Astronomy, Louisiana State University, Baton Rouge, Louisiana, 70803.|Center for Computation & Technology, Louisiana State University, Baton Rouge, Louisiana, 70803.
authors.forename: Mark
authors.initials: M
authors.lastname: Jarrell
mesh_terms: D000465:Algorithms; D000596:Amino Acids / Q000737:chemistry*; D019985:Benchmarking; D030562:Databases, Protein; D055808:Drug Discovery; D057927:Hydrophobic and Hydrophilic Interactions; D008024:Ligands; D062105:Molecular Docking Simulation / Q000706:statistics & numerical data*; D056004:Molecular Dynamics Simulation / Q000706:statistics & numerical data*; D009010:Monte Carlo Method; D011485:Protein Binding; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*; D012372:ROC Curve; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D000596:Amino Acids; D008024:Ligands; D011506:Proteins
keywords: Monte Carlo simulations; descriptor-based force field; force field development; force filed optimization; mixed-resolution modelling; molecular docking