Rapid protein-ligand costructures using chemical shift perturbations

Jaime Stark, Robert Powers

Research output: Contribution to journalArticlepeer-review

47 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)535-545
Number of pages11
JournalJournal of the American Chemical Society
Issue number2
StatePublished - Jan 16 2008

ASJC Scopus subject areas

  • Catalysis
  • General Chemistry
  • Biochemistry
  • Colloid and Surface Chemistry


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