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1.
J Chem Inf Model ; 55(5): 1030-44, 2015 May 26.
Artigo em Inglês | MEDLINE | ID: mdl-25815783

RESUMO

In the current study we have evaluated the applicability of ligand-based virtual screening (LBVS) methods for the identification of small fragment-like biologically active molecules using different similarity descriptors and different consensus scoring approaches. For this purpose, we have evaluated the performance of 14 chemical similarity descriptors in retrospective virtual screening studies to discriminate fragment-like ligands of three membrane-bound receptors from fragments that are experimentally determined to have no affinity for these proteins (true inactives). We used a complete fragment affinity data set of experimentally determined ligands and inactives for two G protein-coupled receptors (GPCRs), the histamine H1 receptor (H1R) and the histamine H4 receptor (H4R), and one ligand-gated ion channel (LGIC), the serotonin receptor (5-HT3AR), to validate our retrospective virtual screening studies. We have exhaustively tested consensus scoring strategies that combine the results of multiple actives (group fusion) or combine different similarity descriptors (similarity fusion), and for the first time systematically evaluated different combinations of group fusion and similarity fusion approaches. Our studies show that for these three case study protein targets both consensus scoring approaches can increase virtual screening enrichments compared to single chemical similarity search methods. Our cheminformatics analyses recommend to use a combination of both group fusion and similarity fusion for prospective ligand-based virtual fragment screening.


Assuntos
Técnicas de Química Combinatória/métodos , Avaliação Pré-Clínica de Medicamentos/métodos , Receptores Histamínicos H1/metabolismo , Receptores 5-HT3 de Serotonina/metabolismo , Interface Usuário-Computador , Consenso , Ligantes
2.
J Med Chem ; 56(11): 4264-76, 2013 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-23668417

RESUMO

The basic methylpiperazine moiety is considered a necessary substructure for high histamine H4 receptor (H4R) affinity. This moiety is however also the metabolic hot spot for various classes of H4R ligands (e.g., indolcarboxamides and pyrimidines). We set out to investigate whether mildly basic 2-aminopyrimidines in combination with the appropriate linker can serve as a replacement for the methylpiperazine moiety. In the series of 2-aminopyrimidines, the introduction of an additional 2-aminopyrimidine moiety in combination with the appropriate linker lead to bispyrimidines displaying pKi values for binding the human H4R up to 8.2. Furthermore, the methylpiperazine replacement results in compounds with improved metabolic properties. The attempt to transfer the knowledge generated in the class of bispyrimidines to the indolecarboxamides failed. Combining the derived structure-activity relationships with homology modeling leads to new detailed insights in the molecular aspects of ligand-H4R binding in general and the binding mode of the described bispyrimidines in specific.


Assuntos
Pirimidinas/química , Receptores Acoplados a Proteínas G/química , Receptores Histamínicos/química , Animais , Sítios de Ligação , Humanos , Técnicas In Vitro , Ligantes , Camundongos , Microssomos Hepáticos/metabolismo , Modelos Moleculares , Pirimidinas/síntese química , Pirimidinas/farmacologia , Teoria Quântica , Ensaio Radioligante , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos/metabolismo , Receptores Histamínicos H4 , Homologia de Sequência de Aminoácidos , Solubilidade , Relação Estrutura-Atividade
3.
ChemMedChem ; 8(1): 49-53, 2013 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-23161844

RESUMO

SAR beyond protein-ligand interactions: By combining structure-affinity relationships, protein-ligand modeling studies, and quantum mechanical calculations, we show that ligand conformational energies and basicity play critical roles in ligand binding to the histamine H4 receptor, a GPCR that plays a key role in inflammation.


Assuntos
Pirimidinas/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos/metabolismo , Células HEK293 , Humanos , Ligantes , Conformação Molecular , Simulação de Acoplamento Molecular , Ligação Proteica , Conformação Proteica , Pirimidinas/química , Receptores Acoplados a Proteínas G/química , Receptores Histamínicos/química , Receptores Histamínicos H4
4.
Eur J Med Chem ; 54: 660-8, 2012 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-22749391

RESUMO

A series of 76 derivatives of the indolecarboxamide 1 were synthesized, which allows a detailed SAR investigation of this well known scaffold. The data enable the definition of a predictive QSAR model which identifies several compounds with an activity comparable to 1. A selection of these new H(4)R antagonists was synthesized and a comparison of predicted and measured values demonstrates the robustness of the model (47-55). In addition to the H(4)-receptor activity general CMC and DMPK properties were investigated. Some of the new analogs are not only excellently soluble, but display a significantly increased half-life in mouse liver microsomes as well. These properties qualify these compounds as a possible new standard for future in vivo studies (e.g 51, 52 and 55). Moreover, the current studies also provide valuable information on the potential receptor ligand interactions between the indolcarboxamides and the H(4)R protein.


Assuntos
Indóis/química , Indóis/metabolismo , Receptores Acoplados a Proteínas G/metabolismo , Receptores Histamínicos/metabolismo , Animais , Estabilidade de Medicamentos , Humanos , Ligantes , Camundongos , Microssomos Hepáticos/metabolismo , Ligação Proteica , Relação Quantitativa Estrutura-Atividade , Receptores Histamínicos H4 , Solubilidade , Relação Estrutura-Atividade
5.
Chem Biodivers ; 6(11): 1960-9, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19937827

RESUMO

ABC-type drug efflux pumps, e.g., ABCB1 (=P-glycoprotein, =MDR1), ABCC1 (=MRP1), and ABCG2 (=MXR, =BCRP), confer a multi-drug resistance (MDR) phenotype to cancer cells. Furthermore, the important contribution of ABC transporters for bioavailability, distribution, elimination, and blood-brain barrier permeation of drug candidates is increasingly recognized. This review presents an overview on the different computational methods and models pursued to predict ABC transporter substrate properties of drug-like compounds. They encompass ligand-based approaches ranging from 'simple rule'-based efforts to sophisticated machine learning methods. Many of these models show excellent performance for the data sets used. However, due to the complex nature of the applied methods, useful interpretation of the models that can be directly translated into chemical structures by the medicinal chemist is rather difficult. Additionally, very recent and promising attempts in the field of structure-based modeling of ABC transporters, which embody homology modeling as well as recently published X-ray structures of murine ABCB1, will be discussed.


Assuntos
Transportadores de Cassetes de Ligação de ATP/metabolismo , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Preparações Farmacêuticas/metabolismo , Absorção , Animais , Simulação por Computador , Previsões , Humanos , Ligantes , Modelos Biológicos , Modelos Moleculares , Farmacocinética , Relação Estrutura-Atividade , Distribuição Tecidual
6.
Bioorg Med Chem ; 17(11): 3987-94, 2009 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-19414267

RESUMO

Previous studies have demonstrated that clobenpropit (N-(4-chlorobenzyl)-S-[3-(4(5)-imidazolyl)propyl]isothiourea) binds to both the human histamine H(3) receptor (H(3)R) and H(4) receptor (H(4)R). In this paper, we describe the synthesis and pharmacological characterization of a series of clobenpropit analogs, which vary in the functional group adjacent to the isothiourea moiety in order to study structural requirements for H(3)R and H(4)R ligands. The compounds show moderate to high affinity for both the human H(3)R and H(4)R. Furthermore, the changes in the functional group attached to the isothiourea moiety modulate the intrinsic activity of the ligands at the H(4)R, ranging from neutral antagonism to full agonism. QSAR models have been generated in order to explain the H(3)R and H(4)R affinities.


Assuntos
Antagonistas dos Receptores Histamínicos H3/química , Imidazóis/síntese química , Imidazóis/farmacologia , Relação Quantitativa Estrutura-Atividade , Receptores Acoplados a Proteínas G/química , Receptores Histamínicos H3/química , Receptores Histamínicos/química , Tioureia/análogos & derivados , Antagonistas dos Receptores Histamínicos H3/farmacologia , Humanos , Imidazóis/química , Ligantes , Masculino , Estrutura Molecular , Ligação Proteica/efeitos dos fármacos , Receptores Histamínicos H4 , Tioureia/síntese química , Tioureia/química , Tioureia/farmacologia
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