[NMR paper] Accounting for Conformational Variability in Protein-Ligand Docking with NMR-Guided Rescoring.

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Accounting for Conformational Variability in Protein-Ligand Docking with NMR-Guided Rescoring.

Related Articles Accounting for Conformational Variability in Protein-Ligand Docking with NMR-Guided Rescoring.

J Am Chem Soc. 2013 Apr 8;

Authors: Skjærven L, Codutti L, Angelini A, Grimaldi M, Latek D, Monecke P, Dreyer MK, Carlomagno T

Abstract
A key component to success in structure-based drug design is reliable information on protein-ligand interactions. Recent development in NMR techniques has accelerated this process by overcoming some of the limitations of X-ray crystallography and computational protein-ligand docking. In this work we present a new scoring protocol based on NMR-derived interligand INPHARMA NOEs to guide the selection of computationally generated docking modes. We demonstrate the performance in a range of scenarios, encompassing traditionally difficult cases such as docking to homology models and ligand dependent domain rearrangements. Ambiguities associated with sparse experimental information are lifted by searching a consensus solution based on simultaneously fitting multiple ligand pairs. This study provides a previously unexplored integration between molecular modeling and experimental data, in which interligand NOEs represent the key element in the rescoring algorithm. The presented protocol should be widely applicable for protein-ligand docking also in a different context from drug design and highlights the important role of NMR-based approaches to describe intermolecular ligand-receptor interactions.


PMID: 23565800 [PubMed - as supplied by publisher]



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