RESUMO
Whilst fragment-based screening has found significant utility in aiding the discovery of high quality hits against a range of targets, the use of this technology in the protein-protein interaction inhibitor field is very much in its infancy. This review aims to highlight the key technologies used to identify fragment hits, such as NMR, SPR, X-ray crystallography and biochemical screening, the fragment-based protein-protein interaction case studies reported to date and, more importantly, the potential of this methodology in unearthing high quality hit molecules in this critical area of drug discovery. In addition, we also discuss some of the key aspects of fragment library design, the composition of a high quality library and suggest ways in which future, more structurally diverse fragments which occupy different regions of chemical space to the vast majority of current fragment libraries may be selected.
Assuntos
Descoberta de Drogas/métodos , Mapeamento de Interação de Proteínas/métodos , Bibliotecas de Moléculas Pequenas , Tecnologia Farmacêutica/métodos , Modelos Moleculares , Estrutura Molecular , Ligação Proteica , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologiaRESUMO
A novel N-aryl piperazine-1-carboxamide series of human CCR2 chemokine receptor antagonists was discovered. Early analogues were potent at CCR2 but also inhibited the hERG cardiac ion channel. Structural modifications which decreased lipophilicity and basicity resulted in the identification of a sub-series with an improved margin over hERG. The pharmacological and pharmacokinetic properties of the lead compound from this series, N-(3,4-dichlorophenyl)-4-[(2R)-4-isopropylpiperazine-2-carbonyl]piperazine-1-carboxamide, are described.
Assuntos
Anti-Inflamatórios/síntese química , Piperazinas/síntese química , Receptores CCR2/antagonistas & inibidores , Animais , Anti-Inflamatórios/farmacocinética , Anti-Inflamatórios/farmacologia , Cálcio/metabolismo , Cães , Desenho de Fármacos , Canais de Potássio Éter-A-Go-Go/antagonistas & inibidores , Canais de Potássio Éter-A-Go-Go/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Inflamação/tratamento farmacológico , Piperazinas/farmacocinética , Piperazinas/farmacologia , Ligação Proteica , Ratos , Receptores CCR2/metabolismoRESUMO
The protein structure guided design of a series of pyrazolo[1,5-a]pyrimidines with high potency for human cyclin-dependent kinase 2 (CDK2) is described. Some examples were shown to inhibit the growth of human colon tumour cells, were equipotent for CDK1 and were selective against GSK-3beta and other kinases.
