RESUMEN
c-di-GMP is an attractive target in the fight against bacterial infections since it is a near ubiquitous second messenger that regulates important cellular processes of pathogens, including biofilm formation and virulence. Screening of a combinatorial peptide library enabled the identification of the proline-rich tetrapeptide Gup-Gup-Nap-Arg, which binds c-di-GMP selectively over other nucleotides in water. Computational and CD spectroscopic studies provided a possible binding mode of the complex and enabled the design of a pentapeptide with even higher binding strength towards c-di-GMP. Biological studies showed that the tetrapeptide inhibits biofilm growth by the opportunistic pathogen P. aeruginosa.
Asunto(s)
GMP Cíclico/análogos & derivados , Péptidos/metabolismo , Prolina/metabolismo , Pseudomonas aeruginosa/metabolismo , Sistemas de Mensajero Secundario , Biopelículas/crecimiento & desarrollo , Dicroismo Circular , GMP Cíclico/metabolismo , Unión Proteica , Pseudomonas aeruginosa/crecimiento & desarrollo , TermodinámicaRESUMEN
Herein we describe the synthesis and structure activity relationship of a new class of FXR agonists identified from a high-throughput screening campaign. Further optimization of the original hits led to molecules that were highly active in an LDL-receptor KO model for dyslipidemia. The most promising candidate is discussed in more detail.
Asunto(s)
Hipoglucemiantes/química , Hipolipemiantes/química , Receptores Citoplasmáticos y Nucleares/agonistas , Administración Oral , Animales , Sitios de Unión , Simulación por Computador , Diabetes Mellitus Experimental/tratamiento farmacológico , Evaluación Preclínica de Medicamentos , Dislipidemias/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Hipolipemiantes/administración & dosificación , Ratones , Ratones Noqueados , Receptores Citoplasmáticos y Nucleares/metabolismo , Receptores de LDL/genética , Receptores de LDL/metabolismo , Relación Estructura-ActividadRESUMEN
This review addresses strategies for the generation of ligands for G-protein-coupled receptors outside classical high-throughput screening and literature based approaches. These range from the chemical intuition-based strategies of endogenous ligand elaboration and privileged structure decoration to the in silico approaches of virtual screening and de novo design. Examples are cited where supporting pharmacological data has been presented.
Asunto(s)
Técnicas Químicas Combinatorias/métodos , Receptores Acoplados a Proteínas G/metabolismo , Tiourea/análogos & derivados , Biología Computacional , Bases de Datos Factuales , Diseño de Fármacos , Imidazoles/química , Ligandos , Estructura Molecular , Piperidinas/química , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/efectos de los fármacos , Receptores Histamínicos H3/metabolismo , Tiourea/químicaRESUMEN
The identification of small-molecule modulators of protein function, and the process of transforming these into high-content lead series, are key activities in modern drug discovery. The decisions taken during this process have far-reaching consequences for success later in lead optimization and even more crucially in clinical development. Recently, there has been an increased focus on these activities due to escalating downstream costs resulting from high clinical failure rates. In addition, the vast emerging opportunities from efforts in functional genomics and proteomics demands a departure from the linear process of identification, evaluation and refinement activities towards a more integrated parallel process. This calls for flexible, fast and cost-effective strategies to meet the demands of producing high-content lead series with improved prospects for clinical success.
Asunto(s)
Diseño de Fármacos , Secuencias de Aminoácidos , Técnicas Químicas Combinatorias , Evaluación Preclínica de Medicamentos , Genómica , ProteómicaRESUMEN
With the successful completion of the human genome sequencing and the resulting plethora of genetic information now available novel technologies and applications have to be established to translate the huge amount of data generated into successful biological and biomedical research programs. The integration of various drug discovery disciplines within the parallel quest for novel targets and new molecular entities has meanwhile given rise to a quite popular term in pharmaceutical research named "chemogenomics". This review article gives an overview of the disciplines involved in this field and discusses the possible implications of this novel paradigm in drug discovery for the near future.
Asunto(s)
Diseño de Fármacos , Genómica/métodos , Algoritmos , Evaluación Preclínica de Medicamentos/métodos , Ligandos , Modelos Moleculares , Interfaz Usuario-ComputadorRESUMEN
The combination of a 3,5-bis(trifluoromethyl)phenyl needle with the spiropyrrolo-pyrrole motive as a privileged GPCR scaffold was the basis for designing a focused combinatorial library targeted towards the neurokinin-1 receptor. A solution- and solid-phase method is described and binding affinities of representative compounds are presented.
Asunto(s)
Pirroles/síntesis química , Pirroles/farmacología , Receptores de Neuroquinina-1/metabolismo , Receptores de Neuroquinina-2/metabolismo , Receptores de Neuroquinina-3/metabolismo , Técnicas Químicas Combinatorias , Proteínas de Unión al GTP/metabolismo , Indicadores y Reactivos , Ligandos , Receptores de Neuroquinina-1/efectos de los fármacos , Receptores de Neuroquinina-2/efectos de los fármacos , Receptores de Neuroquinina-3/efectos de los fármacos , Relación Estructura-ActividadRESUMEN
The combination of the 3,5-bis(trifluoromethyl)phenyl group with a spirohydantoin motive as a central scaffold was the basis for the design of a combinatorial library targeted towards the neurokinin-1 receptor. A solution- and solid-phase procedure is described and binding affinities of representative compounds presented.