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Publication Abstract from PubMed

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.

Accounting for Conformational Variability in Protein-Ligand Docking with NMR-Guided Rescoring.,Skjaerven L, Codutti L, Angelini A, Grimaldi M, Latek D, Monecke P, Dreyer MK, Carlomagno T J Am Chem Soc. 2013 Apr 17;135(15):5819-27. doi: 10.1021/ja4007468. Epub 2013 Apr, 8. PMID:23565800^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.