Rapid Protein−Ligand Costructures Using Chemical Shift Perturbations

Jaime Stark and Robert Powers*
Department of Chemistry, University of Nebraska-Lincoln, Lincoln, Nebraska 68588
J. Am. Chem. Soc., 2008, 130 (2), pp 535–545
DOI: 10.1021/ja0737974
Publication Date (Web): December 19, 2007
Copyright © 2008 American Chemical Society
*

In papers with more than one author, the asterisk indicates the name of the author to whom inquiries about the paper should be addressed.

, rpowers3@unl.edu

Abstract

Abstract Image

Structure-based drug discovery requires the iterative determination of protein−ligand costructures in order to improve the binding affinity and selectivity of potential drug candidates. In general, X-ray and NMR structure determination methods are time consuming and are typically the limiting factor in the drug discovery process. The application of molecular docking simulations to filter and evaluate drug candidates has become a common method to improve the throughput and efficiency of structure-based drug design. Unfortunately, molecular docking methods suffer from common problems that include ambiguous ligand conformers or failure to predict the correct docked structure. A rapid approach to determine accurate protein−ligand costructures is described based on NMR chemical shift perturbation (CSP) data routinely obtained using 2D 1H−15N HSQC spectra in high-throughput ligand affinity screens. The CSP data is used to both guide and filter AutoDock calculations using our AutoDockFilter program. This method is demonstrated for 19 distinct protein−ligand complexes where the docked conformers exhibited an average rmsd of 1.17 ± 0.74 Å relative to the original X-ray structures for the protein−ligand complexes.

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