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1.
Protein Sci ; 24(6): 1004-12, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25761901

RESUMO

The activation/deactivation processes for G-protein coupled receptors (GPCRs) have been computationally studied for several different classes, including rhodopsin, the ß2 adrenergic receptor, and the M2 muscarinic receptor. Despite determined cocrystal structures of the adenosine A2A receptor (A2A AR) in complex with antagonists, agonists and an antibody, the deactivation process of this GPCR is not completely understood. In this study, we investigate the convergence of two apo simulations, one starting with an agonist-bound conformation (PDB: 3QAK)(14) and the other starting with an antagonist-bound conformation (PDB: 3EML)(11) . Despite the two simulations not completely converging, we were able to identify distinct intermediate steps of the deactivation process characterized by the movement of Y288(7.53) in the NPxxY motif. We find that Y288(7.53) contributes to the process by forming hydrogen bonds to residues in transmembrane helices 2 and 7 and losing these interactions upon full deactivation. Y197(5.58) also plays a role in the process by forming a hydrogen bond only once the side chain moves from the lipid interface to the middle of the helical bundle.


Assuntos
Receptor A2A de Adenosina/química , Receptor A2A de Adenosina/metabolismo , Simulação por Computador , Humanos , Ligação de Hidrogênio , Simulação de Dinâmica Molecular , Conformação Proteica
2.
Chem Biol Drug Des ; 83(5): 521-31, 2014 May.
Artigo em Inglês | MEDLINE | ID: mdl-24405985

RESUMO

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are potent anti-HIV chemotherapeutics. Although there are FDA-approved NNRTIs, challenges such as the development of resistance have limited their utility. Here, we describe the identification of novel NNRTIs through a combination of computational and experimental approaches. Based on the known plasticity of the NNRTI binding pocket (NNIBP), we adopted an ensemble-based virtual screening strategy: coupling receptor conformations from 10 X-ray crystal structures with 120 snapshots from a total of 480 ns of molecular dynamics (MD) trajectories. A screening library of 2864 National Cancer Institute (NCI) compounds was built and docked against the ensembles in a hierarchical fashion. Sixteen diverse compounds were tested for their ability to block HIV infection in human tissue cultures using a luciferase-based reporter assay. Three promising compounds were further characterized, using a HIV-1 RT-based polymerase assay, to determine the specific mechanism of inhibition. We found that 2 of the three compounds inhibited the polymerase activity of RT (with potency similar to the positive control, the FDA-approved drug nevirapine). Through a computational approach, we were able to discover two compounds which inhibit HIV replication and block the activity of RT, thus offering the potential for optimization into mature inhibitors.


Assuntos
Transcriptase Reversa do HIV/antagonistas & inibidores , Sítios de Ligação , Avaliação Pré-Clínica de Medicamentos , Células HEK293 , Transcriptase Reversa do HIV/metabolismo , HIV-1/efeitos dos fármacos , HIV-1/enzimologia , Humanos , Simulação de Dinâmica Molecular , Estrutura Terciária de Proteína , Inibidores da Transcriptase Reversa/química , Inibidores da Transcriptase Reversa/farmacologia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Replicação Viral/efeitos dos fármacos
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