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

RESUMEN

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.


Asunto(s)
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
2.
J Biol Chem ; 279(43): 45121-9, 2004 Oct 22.
Artículo en Inglés | MEDLINE | ID: mdl-15308656

RESUMEN

Tumor necrosis factor-alpha (TNF-alpha)-converting enzyme (TACE, ADAM-17) is a zinc-dependent ADAM (a disintegrin and metalloproteinase) metalloproteinase (MP) of the metzincin superfamily. The enzyme regulates the shedding of a variety of cell surface-anchored molecules such as cytokines, growth factors, and receptors. The activities of the MPs are modulated by the endogenous inhibitors, the tissue inhibitor of metalloproteinases (TIMPs). Among the four mammalian TIMPs (TIMP-1 to -4), TACE is selectively inhibited by TIMP-3. The rationale for such selectivity is not fully understood. Here, we examine the molecular basis of TIMP-TACE selectivity using TIMP-2 as the scaffold. By systematically replacing the surface epitopes of TIMP-2 with those of TIMP-3 and a TIMP-1 variant V4S/TIMP-3 AB-loop/V69L/T98L, we created a novel TIMP-2 mutant that exhibits inhibitory potency almost equal to that of the TIMP-3. The affinity of the mutant with TACE is 1.49 nm, a marked improvement in comparison to that of the wild-type protein (Ki 893 nM). The inhibitory pattern of the mutant is typical of that of a slow, tight binding inhibitor. We identify phenylalanine 34, a residue unique to the TIMP-3 AB-loop, as a vital element in TACE association. Mutagenesis carried out on leucine 100 also upholds our previous findings that a leucine on the EF-loop is critical for TACE recognition. Replacement of the residue by other amino acids resulted in a dramatic decrease in binding affinity, although isoleucine (L100I) and methionine (L100M) are still capable of producing the slow, tight binding effect. Our findings here represent a significant advance toward designing tailor-made TIMPs for specific MP targeting.


Asunto(s)
Inhibidor Tisular de Metaloproteinasa-2/química , Proteínas ADAM , Proteína ADAM17 , Secuencia de Aminoácidos , Dicroismo Circular , ADN/química , ADN Complementario/metabolismo , Epítopos/química , Escherichia coli/metabolismo , Humanos , Isoleucina/química , Cinética , Leucina/química , Metaloendopeptidasas/química , Metionina/química , Modelos Químicos , Modelos Moleculares , Datos de Secuencia Molecular , Mutagénesis Sitio-Dirigida , Mutación , Fenilalanina/química , Unión Proteica , Desnaturalización Proteica , Pliegue de Proteína , Estructura Terciaria de Proteína , Análisis de Secuencia de ADN , Homología de Secuencia de Aminoácido , Treonina/química , Factores de Tiempo , Inhibidor Tisular de Metaloproteinasa-2/metabolismo
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