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J Chem Inf Model ; 48(11): 2214-25, 2008 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-18954138


In the validation of protein-ligand docking protocols, performance is mostly measured against native protein conformers, i.e. each ligand is docked into the protein conformation from the structure that contained that ligand. In real-life applications, however, ligands are docked against non-native conformations of the protein, i.e. the apo structure or a structure of a different protein-ligand complex. Here, we have constructed an extensive test set for assessing docking performance against non-native protein conformations. This new test set is built on the Astex Diverse Set (which we recently constructed for assessing native docking performance) and contains 1112 non-native structures for 65 drug targets. Using the protein-ligand docking program GOLD, the Astex Diverse Set and the new Astex Non-native Set, we established that, whereas docking performance (top-ranked solution within 2 A rmsd of the experimental binding mode) is approximately 80% for native docking, this drops to 61% for non-native docking. A similar drop-off is observed for sampling performance (any solution within 2 A): 91% for native docking vs 72% for non-native docking. No significant differences were observed between docking performance against apo and nonapo structures. We found that, whereas small variations in protein conformation are generally tolerated by our rigid docking protocol, larger protein movements result in a catastrophic drop-off in performance. Some docking performance and nearly all sampling performance can be recovered by considering dockings produced against a small number of non-native structures simultaneously. Docking against non-native structures of complexes containing ligands that are similar to the docked ligand also significantly improves both docking performance and sampling performance.

Proteínas/química , Sitios de Unión , Simulación por Computador , Bases de Datos de Proteínas , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/estadística & datos numéricos , Informática , Ligandos , Modelos Moleculares , Conformación Proteica , Programas Informáticos , Interfaz Usuario-Computador
Curr Opin Chem Biol ; 11(5): 485-93, 2007 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-17851109


Approaches which start from a study of the interaction of very simple molecules (fragments) with the protein target are proving to be valuable additions to drug design. Fragment-based screening allows the complementarity between a protein active site and drug-like molecules to be rapidly and effectively explored, using structural methods. Recent improvements in the intensities of laboratory X-ray sources permits the collection of greater amounts of high-quality diffraction data and have been matched by developments in automation, crystallisation and data analysis. Developments in NMR screening, including the use of cryogenically cooled NMR probes and (19)F-containing reporter molecules have expanded the scope of this technique, while increasing the availability of binding site and quantitative affinity data for the fragments. Application of these methods has led to a greater knowledge of the chemical variety, structural features and energetics of protein-fragment interactions. While fragment-based screening has already been shown to reduce the timescales of the drug discovery process, a more detailed characterisation of fragment screening hits can reveal unexpected similarities between fragment chemotypes and protein active sites leading to improved understanding of the pharmacophores and the re-use of this information against other protein targets.

Evaluación Preclínica de Medicamentos/métodos , Proteínas/química , Sitios de Unión , Cristalografía por Rayos X , Ligandos , Espectroscopía de Resonancia Magnética
Curr Opin Drug Discov Devel ; 7(4): 404-10, 2004 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-15338949


Fragment-based ligand screening can be a highly effective strategy for drug discovery. In general, fragment hits interact efficiently with the target, and although the potency of these small binders is often low, their optimization into potent leads is tractable. For a hit optimization phase to take full advantage of a good quality fragment binder, we believe it is essential to obtain reliable structural data for the hits. In this review, we describe the methods used for structure-based fragment screening and fragment-to-lead optimization and discuss a number of applications from the literature.

Proteínas Portadoras/química , Diseño de Fármacos , Evaluación Preclínica de Medicamentos/métodos , Relación Estructura-Actividad , Sitios de Unión/efectos de los fármacos , Sitios de Unión/fisiología , Biología Computacional/métodos , Cristalografía por Rayos X/métodos , Espectroscopía de Resonancia Magnética/métodos , Espectrometría de Masas/métodos , Modelos Químicos , Modelos Estructurales