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Bioorg Med Chem Lett ; 41: 127973, 2021 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-33753261


α1-antitrypsin deficiency is characterised by the misfolding and intracellular polymerisation of mutant α1-antitrypsin protein within the endoplasmic reticulum (ER) of hepatocytes. Small molecules that bind and stabilise Z α1-antitrypsin were identified via a DNA-encoded library screen. A subsequent structure based optimisation led to a series of highly potent, selective and cellular active α1-antitrypsin correctors.

Diseño de Fármacos , Pliegue de Proteína , alfa 1-Antitripsina/metabolismo , Cristalización , Desarrollo de Medicamentos/métodos , Evaluación Preclínica de Medicamentos , Retículo Endoplásmico/metabolismo , Biblioteca de Genes , Hepatocitos/metabolismo , Humanos , Modelos Moleculares , Conformación Proteica , alfa 1-Antitripsina/genética
Bioorg Med Chem Lett ; 29(20): 126675, 2019 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-31521475


The connection between Netherton syndrome and overactivation of epidermal/dermal proteases, particularly Kallikrein 5 (KLK5) has been well established and it is expected that a KLK5 inhibitor would improve the dermal barrier and also reduce the pain and itch that afflict Netherton syndrome patients. One of the challenges of covalent protease inhibitors has been achieving selectivity over closely related targets. In this paper we describe the use of structural insight to design and develop a selective and highly potent reversibly covalent KLK5 inhibitor from an initial weakly binding fragment.

Benzamidinas/química , Calicreínas/antagonistas & inhibidores , Síndrome de Netherton/tratamiento farmacológico , Inhibidores de Serina Proteinasa/química , Secuencia de Aminoácidos , Benzamidinas/farmacología , Sitios de Unión , Evaluación Preclínica de Medicamentos , Humanos , Isomerismo , Modelos Moleculares , Estructura Molecular , Mutación , Unión Proteica , Inhibidor de Serinpeptidasas Tipo Kazal-5/genética , Inhibidores de Serina Proteinasa/farmacología , Relación Estructura-Actividad
J Med Chem ; 59(11): 5356-67, 2016 06 09.
Artículo en Inglés | MEDLINE | ID: mdl-27167608


Elevated levels of human lipoprotein-associated phospholipase A2 (Lp-PLA2) are associated with cardiovascular disease and dementia. A fragment screen was conducted against Lp-PLA2 in order to identify novel inhibitors. Multiple fragment hits were observed in different regions of the active site, including some hits that bound in a pocket created by movement of a protein side chain (approximately 13 Å from the catalytic residue Ser273). Using structure guided design, we optimized a fragment that bound in this pocket to generate a novel low nanomolar chemotype, which did not interact with the catalytic residues.

1-Alquil-2-acetilglicerofosfocolina Esterasa/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Pirazoles/farmacología , Tiazoles/farmacología , 1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , Sitios de Unión/efectos de los fármacos , Cristalografía por Rayos X , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Humanos , Modelos Moleculares , Estructura Molecular , Pirazoles/síntesis química , Pirazoles/química , Relación Estructura-Actividad , Tiazoles/síntesis química , Tiazoles/química