Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 6 de 6
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
PLoS One ; 10(3): e0118200, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25729848

RESUMO

The human bitter taste receptor hTAS2R39 can be activated by many dietary (iso)flavonoids. Furthermore, hTAS2R39 activity can be blocked by 6-methoxyflavanones, 4'-fluoro-6-methoxyflavanone in particular. A structure-based pharmacophore model of the hTAS2R39 binding pocket was built using Snooker software, which has been used successfully before for drug design of GPCRs of the rhodopsin subfamily. For the validation of the model, two sets of compounds, both of which contained actives and inactives, were used: (i) an (iso)flavonoid-dedicated set, and (ii) a more generic, structurally diverse set. Agonists were characterized by their linear binding geometry and the fact that they bound deeply in the hTAS2R39 pocket, mapping the hydrogen donor feature based on T5.45 and N3.36, analogues of which have been proposed to play a key role in activation of GPCRs. Blockers lack hydrogen-bond donors enabling contact to the receptor. Furthermore, they had a crooked geometry, which could sterically hinder movement of the TM domains upon receptor activation. Our results reveal characteristics of hTAS2R39 agonist and bitter blocker binding, which might facilitate the development of blockers suitable to counter the bitterness of dietary hTAS2R39 agonists in food applications.


Assuntos
Receptores de Superfície Celular/metabolismo , Software , Sítios de Ligação , Desenho de Fármacos , Flavanonas/química , Flavanonas/metabolismo , Flavonoides/química , Flavonoides/metabolismo , Humanos , Simulação de Acoplamento Molecular , Ligação Proteica , Estrutura Terciária de Proteína , Receptores de Superfície Celular/agonistas , Receptores de Superfície Celular/antagonistas & inibidores
2.
J Chem Inf Model ; 52(6): 1607-20, 2012 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-22646988

RESUMO

The pharmacophore concept is of central importance in computer-aided drug design (CADD) mainly because of its successful application in medicinal chemistry and, in particular, high-throughput virtual screening (HTVS). The simplicity of the pharmacophore definition enables the complexity of molecular interactions between ligand and receptor to be reduced to a handful set of features. With many pharmacophore screening softwares available, it is of the utmost interest to explore the behavior of these tools when applied to different biological systems. In this work, we present a comparative analysis of eight pharmacophore screening algorithms (Catalyst, Unity, LigandScout, Phase, Pharao, MOE, Pharmer, and POT) for their use in typical HTVS campaigns against four different biological targets by using default settings. The results herein presented show how the performance of each pharmacophore screening tool might be specifically related to factors such as the characteristics of the binding pocket, the use of specific pharmacophore features, and the use of these techniques in specific steps/contexts of the drug discovery pipeline. Algorithms with rmsd-based scoring functions are able to predict more compound poses correctly as overlay-based scoring functions. However, the ratio of correctly predicted compound poses versus incorrectly predicted poses is better for overlay-based scoring functions that also ensure better performances in compound library enrichments. While the ensemble of these observations can be used to choose the most appropriate class of algorithm for specific virtual screening projects, we remarked that pharmacophore algorithms are often equally good, and in this respect, we also analyzed how pharmacophore algorithms can be combined together in order to increase the success of hit compound identification. This study provides a valuable benchmark set for further developments in the field of pharmacophore search algorithms, e.g., by using pose predictions and compound library enrichment criteria.


Assuntos
Química Farmacêutica , Desenho de Fármacos , Algoritmos , Desenho Assistido por Computador , Avaliação Pré-Clínica de Medicamentos
3.
J Med Chem ; 55(11): 5311-25, 2012 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-22563707

RESUMO

We present the systematic prospective evaluation of a protein-based and a ligand-based virtual screening platform against a set of three G-protein-coupled receptors (GPCRs): the ß-2 adrenoreceptor (ADRB2), the adenosine A(2A) receptor (AA2AR), and the sphingosine 1-phosphate receptor (S1PR1). Novel bioactive compounds were identified using a consensus scoring procedure combining ligand-based (frequent substructure ranking) and structure-based (Snooker) tools, and all 900 selected compounds were screened against all three receptors. A striking number of ligands showed affinity/activity for GPCRs other than the intended target, which could be partly attributed to the fuzziness and overlap of protein-based pharmacophore models. Surprisingly, the phosphodiesterase 5 (PDE5) inhibitor sildenafil was found to possess submicromolar affinity for AA2AR. Overall, this is one of the first published prospective chemogenomics studies that demonstrate the identification of novel cross-pharmacology between unrelated protein targets. The lessons learned from this study can be used to guide future virtual ligand design efforts.


Assuntos
Bases de Dados Factuais , Desenho de Fármacos , Modelos Moleculares , Relação Quantitativa Estrutura-Atividade , Receptores A2 de Adenosina/química , Receptores Adrenérgicos beta 2/química , Receptores de Lisoesfingolipídeo/química , Agonistas do Receptor A2 de Adenosina/química , Antagonistas do Receptor A2 de Adenosina/química , Agonistas de Receptores Adrenérgicos beta 2/química , Antagonistas de Receptores Adrenérgicos beta 2/química , Animais , Células CHO , Cricetinae , Cricetulus , Agonismo Parcial de Drogas , Células HEK293 , Ensaios de Triagem em Larga Escala , Humanos , Ligantes , Estrutura Molecular , Inibidores da Fosfodiesterase 5/química , Piperazinas/química , Piperazinas/metabolismo , Purinas/química , Purinas/metabolismo , Ensaio Radioligante , Receptores A2 de Adenosina/metabolismo , Receptores Adrenérgicos beta 2/metabolismo , Receptores de Lisoesfingolipídeo/agonistas , Receptores de Lisoesfingolipídeo/metabolismo , Citrato de Sildenafila , Processos Estocásticos , Sulfonas/química , Sulfonas/metabolismo
4.
BMC Bioinformatics ; 12: 332, 2011 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-21831265

RESUMO

BACKGROUND: G-protein coupled receptors (GPCRs) are involved in many different physiological processes and their function can be modulated by small molecules which bind in the transmembrane (TM) domain. Because of their structural and sequence conservation, the TM domains are often used in bioinformatics approaches to first create a multiple sequence alignment (MSA) and subsequently identify ligand binding positions. So far methods have been developed to predict the common ligand binding residue positions for class A GPCRs. RESULTS: Here we present 1) ss-TEA, a method to identify specific ligand binding residue positions for any receptor, predicated on high quality sequence information. 2) The largest MSA of class A non olfactory GPCRs in the public domain consisting of 13324 sequences covering most of the species homologues of the human set of GPCRs. A set of ligand binding residue positions extracted from literature of 10 different receptors shows that our method has the best ligand binding residue prediction for 9 of these 10 receptors compared to another state-of-the-art method. CONCLUSIONS: The combination of the large multi species alignment and the newly introduced residue selection method ss-TEA can be used to rapidly identify subfamily specific ligand binding residues. This approach can aid the design of site directed mutagenesis experiments, explain receptor function and improve modelling. The method is also available online via GPCRDB at http://www.gpcr.org/7tm/.


Assuntos
Entropia , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Alinhamento de Sequência/métodos , Animais , Humanos , Ligantes , Modelos Moleculares , Ligação Proteica , Receptores Acoplados a Proteínas G/classificação
5.
J Chem Inf Model ; 51(9): 2277-92, 2011 Sep 26.
Artigo em Inglês | MEDLINE | ID: mdl-21866955

RESUMO

G-protein coupled receptors (GPCRs) are important drug targets for various diseases and of major interest to pharmaceutical companies. The function of individual members of this protein family can be modulated by the binding of small molecules at the extracellular side of the structurally conserved transmembrane (TM) domain. Here, we present Snooker, a structure-based approach to generate pharmacophore hypotheses for compounds binding to this extracellular side of the TM domain. Snooker does not require knowledge of ligands, is therefore suitable for apo-proteins, and can be applied to all receptors of the GPCR protein family. The method comprises the construction of a homology model of the TM domains and prioritization of residues on the probability of being ligand binding. Subsequently, protein properties are converted to ligand space, and pharmacophore features are generated at positions where protein ligand interactions are likely. Using this semiautomated knowledge-driven bioinformatics approach we have created pharmacophore hypotheses for 15 different GPCRs from several different subfamilies. For the beta-2-adrenergic receptor we show that ligand poses predicted by Snooker pharmacophore hypotheses reproduce literature supported binding modes for ∼75% of compounds fulfilling pharmacophore constraints. All 15 pharmacophore hypotheses represent interactions with essential residues for ligand binding as observed in mutagenesis experiments and compound selections based on these hypotheses are shown to be target specific. For 8 out of 15 targets enrichment factors above 10-fold are observed in the top 0.5% ranked compounds in a virtual screen. Additionally, prospectively predicted ligand binding poses in the human dopamine D3 receptor based on Snooker pharmacophores were ranked among the best models in the community wide GPCR dock 2010.


Assuntos
Receptores Acoplados a Proteínas G/química , Ligantes , Modelos Moleculares , Mutagênese , Ligação Proteica , Conformação Proteica , Receptores Acoplados a Proteínas G/genética
6.
J Comput Aided Mol Des ; 21(8): 455-71, 2007 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-17646925

RESUMO

Aldosterone is synthesised by aldosterone synthase (CYP11B2). CYP11B2 has a highly homologous isoform, steroid 11beta-hydroxylase (CYP11B1), which is responsible for the biosynthesis of aldosterone precursors and glucocorticoids. To investigate aldosterone biosynthesis and facilitate the search for selective CYP11B2 inhibitors, we constructed three-dimensional models for CYP11B1 and CYP11B2 for both human and rat. The models were constructed based on the crystal structure of Pseudomonas Putida CYP101 and Oryctolagus Cuniculus CYP2C5. Small steric active site differences between the isoforms were found to be the most important determinants for the regioselective steroid synthesis. A possible explanation for these steric differences for the selective synthesis of aldosterone by CYP11B2 is presented. The activities of the known CYP11B inhibitors metyrapone, R-etomidate, R-fadrazole and S-fadrazole were determined using assays of V79MZ cells that express human CYP11B1 and CYP11B2, respectively. By investigating the inhibitors in the human CYP11B models using molecular docking and molecular dynamics simulations we were able to predict a similar trend in potency for the inhibitors as found in the in vitro assays. Importantly, based on the docking and dynamics simulations it is possible to understand the enantioselectivity of the human enzymes for the inhibitor fadrazole, the R-enantiomer being selective for CYP11B2 and the S-enantiomer being selective for CYP11B1.


Assuntos
Simulação por Computador , Citocromo P-450 CYP11B2/química , Esteroide 11-beta-Hidroxilase/química , Sequência de Aminoácidos , Animais , Domínio Catalítico/genética , Citocromo P-450 CYP11B2/antagonistas & inibidores , Citocromo P-450 CYP11B2/genética , Citocromo P-450 CYP11B2/metabolismo , Desenho de Fármacos , Humanos , Ligantes , Modelos Moleculares , Dados de Sequência Molecular , Ratos , Homologia de Sequência de Aminoácidos , Esteroide 11-beta-Hidroxilase/antagonistas & inibidores , Esteroide 11-beta-Hidroxilase/genética , Esteroide 11-beta-Hidroxilase/metabolismo , Termodinâmica
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...