title: A Comprehensive Docking and MM/GBSA Rescoring Study of Ligand Recognition upon Binding Antithrombin.
abstract: BACKGROUND
  A high-throughput virtual screening pipeline has been extended from single energetically minimized structure Molecular Mechanics/Generalized Born Surface Area (MM/GBSA) rescoring to ensemble-average MM/GBSA rescoring. The correlation coefficient (R2) of calculated and experimental binding free energies for a series of antithrombin ligands has been improved from 0.36 to 0.69 when switching from the single-structure MM/GBSA rescoring to ensemble-average one. The electrostatic interactions in both solute and solvent are identified to play an important role in determining the binding free energy after the decomposition of the calculated binding free energy. The increasing negative charge of the compounds provides a more favorable electrostatic energy change but creates a higher penalty for the solvation free energy. Such a penalty is compensated by the electrostatic energy change, which results in a better binding affinity. A highly hydrophobic ligand is determined by the docking program to be a non-specific binder.
  
  
  RESULTS
  Our results have demonstrated that it is very important to keep a few top poses for rescoring, if the binding is non-specific or the binding mode is not well determined by the docking calculation.
authors.affiliation: Biosciences and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory (LLNL), Livermore, CA, United States.
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Bioinformatics and High Performance Computing Research Group, Department of Computer Science, Universidad Católica San Antonio de Murcia (UCAM), Spain.
authors.forename: Horacio
authors.initials: H
authors.lastname: Perez-Sanchez
authors.affiliation: Biosciences and Biotechnology Division, Physical and Life Sciences Directorate, Lawrence Livermore National Laboratory (LLNL), Livermore 94550, CA, United States.
authors.forename: Felice C
authors.initials: FC
authors.lastname: Lightstone
mesh_terms: D000991:Antithrombins / Q000737:chemistry*; D001665:Binding Sites; D057166:High-Throughput Screening Assays; D008024:Ligands; D062105:Molecular Docking Simulation; D055672:Static Electricity; D013816:Thermodynamics
chemical_list: D000991:Antithrombins; D008024:Ligands
keywords: Antithrombin.; BINDSURF; Binding Affinity; Docking; MM/GBSA; Molecular Dynamics; Rescoring; VinaLC