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Grand Canonical Monte Carlo Simulation of Ligand−Protein Binding

Matthew Clark,* Frank Guarnieri, Igor Shkurko, and Jeff Wiseman

Locus Pharmaceuticals Four Valley Square, 512 Township Line Road, Blue Bell, Pennsylvania 19422

J. Chem. Inf. Model., 2006, 46 (1), pp 231–242

DOI: 10.1021/ci050268f

Publication Date (Web): November 24, 2005

Corresponding author e-mail: mclark@locuspharma.com.

Abstract

A new application of the grand canonical thermodynamics ensemble to compute ligand−protein binding is described. The described method is sufficiently rapid that it is practical to compute ligand−protein binding free energies for a large number of poses over the entire protein surface, thus identifying multiple putative ligand binding sites. In addition, the method computes binding free energies for a large number of poses. The method is demonstrated by the simulation of two protein−ligand systems, thermolysin and T4 lysozyme, for which there is extensive thermodynamic and crystallographic data for the binding of small, rigid ligands. These low-molecular-weight ligands correspond to the molecular fragments used in computational fragment-based drug design. The simulations correctly identified the experimental binding poses and rank ordered the affinities of ligands in each of these systems.

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Published In Issue January 23, 2006
Received June 27, 2005

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Article

Grand Canonical Monte Carlo Simulation of Ligand−Protein Binding

Abstract

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Related Content

On Sampling of Fragment Space

On Evaluating Molecular-Docking Methods for Pose Prediction and Enrichment Factors

Flux (1): A Virtual Synthesis Scheme for Fragment-Based de Novo Design

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