Assuntos
Antivirais/análise , Tratamento Farmacológico da COVID-19 , Comportamento Cooperativo , Descoberta de Drogas/métodos , Descoberta de Drogas/organização & administração , Avaliação Pré-Clínica de Medicamentos/métodos , Publicação de Acesso Aberto , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , COVID-19/epidemiologia , COVID-19/virologia , Ensaios Clínicos como Assunto , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , Crowdsourcing , Cristalografia por Raios X/instrumentação , Reposicionamento de Medicamentos , Objetivos , Humanos , Cooperação Internacional , Israel/epidemiologia , SARS-CoV-2/genética , SARS-CoV-2/isolamento & purificação , Mídias Sociais , Síncrotrons , Fatores de Tempo , Reino Unido/epidemiologia , Comunicação por Videoconferência , Voluntários , Organização Mundial da Saúde/organização & administraçãoRESUMO
Double electron-electron resonance in conjunction with site-directed spin labeling has been used to probe natural conformational sampling of the human tumor necrosis factor α trimer. We suggest a previously unreported, predeoligomerization conformation of the trimer that has been shown to be sampled at low frequency. A model of this trimeric state has been constructed based on crystal structures using the double-electron-electron-resonance distances. The model shows one of the protomers to be rotated and tilted outward at the tip end, leading to a breaking of the trimerous symmetry and distortion at a receptor-binding interface. The new structure offers opportunities to modulate the biological activity of tumor necrosis factor α through stabilization of the distorted trimer with small molecules.
Assuntos
Espectroscopia de Ressonância de Spin Eletrônica , Fator de Necrose Tumoral alfa/metabolismo , Escherichia coli , Humanos , Modelos Moleculares , Mutação , Multimerização Proteica , Estabilidade Proteica , Estrutura Quaternária de Proteína , Marcadores de Spin , Fator de Necrose Tumoral alfa/química , Fator de Necrose Tumoral alfa/genéticaRESUMO
We report the results of the COVID Moonshot, a fully open-science, crowdsourced, and structure-enabled drug discovery campaign targeting the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease. We discovered a noncovalent, nonpeptidic inhibitor scaffold with lead-like properties that is differentiated from current main protease inhibitors. Our approach leveraged crowdsourcing, machine learning, exascale molecular simulations, and high-throughput structural biology and chemistry. We generated a detailed map of the structural plasticity of the SARS-CoV-2 main protease, extensive structure-activity relationships for multiple chemotypes, and a wealth of biochemical activity data. All compound designs (>18,000 designs), crystallographic data (>490 ligand-bound x-ray structures), assay data (>10,000 measurements), and synthesized molecules (>2400 compounds) for this campaign were shared rapidly and openly, creating a rich, open, and intellectual property-free knowledge base for future anticoronavirus drug discovery.
Assuntos
Tratamento Farmacológico da COVID-19 , Proteases 3C de Coronavírus , Inibidores de Protease de Coronavírus , Descoberta de Drogas , SARS-CoV-2 , Humanos , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases 3C de Coronavírus/química , Simulação de Acoplamento Molecular , Inibidores de Protease de Coronavírus/síntese química , Inibidores de Protease de Coronavírus/química , Inibidores de Protease de Coronavírus/farmacologia , Relação Estrutura-Atividade , Cristalografia por Raios XRESUMO
A series of quinoxaline inhibitors of c-Met kinase is described. The postulated binding mode was confirmed by an X-ray crystal structure and optimisation of the series was performed on the basis of this structure. Future directions for development of the series are discussed together with the identification of a novel quinoline scaffold.
Assuntos
Inibidores Enzimáticos/farmacologia , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Quinoxalinas/farmacologia , Cristalografia por Raios X , Descoberta de Drogas , Inibidores Enzimáticos/química , Quinoxalinas/química , Relação Estrutura-AtividadeRESUMO
A series of 4-azaindole inhibitors of c-Met kinase is described. The postulated binding mode was confirmed by an X-ray crystal structure and series optimisation was performed on the basis of this structure. Future directions for series development are discussed.
Assuntos
Indóis/química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-met/antagonistas & inibidores , Linhagem Celular Tumoral , Simulação por Computador , Cristalografia por Raios X , Descoberta de Drogas , Humanos , Indóis/síntese química , Indóis/farmacologia , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Relação Estrutura-AtividadeRESUMO
The primary target of a novel series of immunosuppressive 7-piperazin-1-ylthiazolo[5,4- d]pyrimidin-5-amines was identified as the lipid kinase, PI4KIIIß. Evaluation of the series highlighted their poor solubility and unwanted off-target activities. A medicinal chemistry strategy was put in place to optimize physicochemical properties within the series, while maintaining potency and improving selectivity over other lipid kinases. Compound 22 was initially identified and profiled in vivo, before further modifications led to the discovery of 44 (UCB9608), a vastly more soluble, selective compound with improved metabolic stability and excellent pharmacokinetic profile. A co-crystal structure of 44 with PI4KIIIß was solved, confirming the binding mode of this class of inhibitor. The much-improved in vivo profile of 44 positions it as an ideal tool compound to further establish the link between PI4KIIIß inhibition and prolonged allogeneic organ engraftment, and suppression of immune responses in vivo.
Assuntos
Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/farmacocinética , Fosfotransferases (Aceptor do Grupo Álcool)/antagonistas & inibidores , Piperazinas/farmacologia , Piperazinas/farmacocinética , Piperidinas/farmacologia , Transplante Homólogo , Administração Oral , Animais , Disponibilidade Biológica , Inibidores Enzimáticos/administração & dosagem , Inibidores Enzimáticos/metabolismo , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/metabolismo , Imunossupressores/farmacocinética , Imunossupressores/farmacologia , Camundongos , Simulação de Acoplamento Molecular , Fosfotransferases (Aceptor do Grupo Álcool)/química , Fosfotransferases (Aceptor do Grupo Álcool)/metabolismo , Piperazinas/administração & dosagem , Piperazinas/metabolismo , Piperidinas/administração & dosagem , Piperidinas/metabolismo , Conformação ProteicaRESUMO
Computational searches for novel ligands for a given protein binding site have become ubiquitous in the pharmaceutical industry, and are potentially equally useful in helping identify small-molecule tools for biology. Here we describe the steps needed to carry out a high-throughput docking (HTD) or three-dimensional (3D) pharmacophore virtual screen starting with a model of the target protein's structure. The advice given is, in most cases, software independent but some tips are provided which apply only to certain popular programs. Useful work can be carried out using free programs on a modest workstation. Of course, any resultant "hits" remain in the virtual world until they are experimentally tested.