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Biochem Soc Trans ; 48(1): 271-280, 2020 02 28.
Artículo en Inglés | MEDLINE | ID: mdl-31985743


Fragment-based drug discovery (FBDD) has become a mainstream technology for the identification of chemical hit matter in drug discovery programs. To date, the food and drug administration has approved four drugs, and over forty compounds are in clinical studies that can trace their origins to a fragment-based screen. The challenges associated with implementing an FBDD approach are many and diverse, ranging from the library design to developing methods for identifying weak affinity compounds. In this article, we give an overview of current progress in fragment library design, fragment to lead optimisation and on the advancement in techniques used for screening. Finally, we will comment on the future opportunities and challenges in this field.

Diseño de Fármacos , Descubrimiento de Drogas/métodos , Descubrimiento de Drogas/tendencias , Bibliotecas de Moléculas Pequeñas/química , Cristalografía por Rayos X , Aprobación de Drogas , Evaluación Preclínica de Medicamentos/métodos , Ensayos Analíticos de Alto Rendimiento/tendencias , Humanos , Espectroscopía de Resonancia Magnética , Unión Proteica
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
Chembiochem ; 6(3): 506-12, 2005 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-15696598


This article describes the application of a high-throughput X-ray crystallographic fragment-based screening methodology to identify low-molecular-weight leads for structure-based optimisation into protein kinase inhibitors. The identification of two novel p38alpha MAP kinase inhibitors (with IC50=65 and 150 nM) starting from low-molecular-weight fragments is described.

Evaluación Preclínica de Medicamentos/métodos , Proteína Quinasa 14 Activada por Mitógenos/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/química , Inhibidores de Proteínas Quinasas/farmacología , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos/instrumentación , Humanos , Proteína Quinasa 14 Activada por Mitógenos/química , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Fragmentos de Péptidos/antagonistas & inhibidores , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo