RESUMEN
As a major class of medicine for treating the lethal type of castration-resistant prostate cancer (PCa), long-term use of androgen receptor (AR) antagonists commonly leads to antiandrogen resistance. When AR signaling pathway is blocked by AR-targeted therapy, glucocorticoid receptor (GR) could compensate for AR function especially at the late stage of PCa. AR-GR dual antagonist is expected to be a good solution for this situation. Nevertheless, no effective non-steroidal AR-GR dual antagonist has been reported so far. In this study, an AR-GR dual binder H18 was first discovered by combining structure-based virtual screening and biological evaluation. Then with the aid of computationally guided design, the AR-GR dual antagonist HD57 was finally identified with antagonistic activity towards both AR (IC50 = 0.394 µM) and GR (IC50 = 17.81 µM). Moreover, HD57 could effectively antagonize various clinically relevant AR mutants. Further molecular dynamics simulation provided more atomic insights into the mode of action of HD57. Our research presents an efficient and rational strategy for discovering novel AR-GR dual antagonists, and the new scaffold provides important clues for the development of novel therapeutics for castration-resistant PCa.
Asunto(s)
Antagonistas de Andrógenos , Neoplasias de la Próstata , Masculino , Humanos , Antagonistas de Andrógenos/farmacología , Receptores de Glucocorticoides/metabolismo , Receptores Androgénicos/metabolismo , Antagonistas de Receptores Androgénicos/farmacología , Neoplasias de la Próstata/metabolismo , Línea Celular TumoralRESUMEN
The novel coronavirus disease has spread rapidly and caused sustained pressure on economic and medical resources to many countries. Vaccines and effective drugs are needed to fight against the epidemic. Traditional Chinese Medicine (TCM) plays an important and effective role in the treatment of COVID-19. Therefore, the active components of TCM are potential structural basis for the discovery of antiviral drugs. Through screening by molecular docking, Oleanolic acid, Tryptanthrin, Chrysophanol and Rhein were found to have better spike protein and ACE2 inhibitory activity, which could block the invasion and recognition of SARS-CoV-2 at the same time, should be investigated as antiviral candidates.
Asunto(s)
Enzima Convertidora de Angiotensina 2 , COVID-19 , Glicoproteína de la Espiga del Coronavirus , Enzima Convertidora de Angiotensina 2/antagonistas & inhibidores , Antivirales/química , Antivirales/farmacología , Glicoproteínas/metabolismo , Humanos , Simulación del Acoplamiento Molecular , Unión Proteica , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/antagonistas & inhibidores , Glicoproteína de la Espiga del Coronavirus/metabolismoRESUMEN
Dual- or multi-target drugs are particularly promising for the treatment of complex diseases such as (neuro)inflammatory disorders. In the present study, we identified dual antagonists for two related pro-inflammatory G protein-coupled receptors (GPCRs), the purinergic receptor P2Y2 receptor, and the orphan receptor GPR17. Based on the lead compound suramin small molecules were designed, synthesized, and modified, including benzenesulfonate, benzenesulfonamide, dibenzamide and diphenylurea derivatives. Structure-activity relationship studies identified 3-nitrophenyl 4-benzamidobenzenesulfonic acid derivatives as dual P2Y2R/GPR17 antagonists. In particular, 3-nitrophenyl 4-(4-chlorobenzamido)benzenesulfonate (14l, IC50 3.01⯵Mâ¯at P2Y2R, and 3.37â¯â¯µMâ¯at GPR17) and 3-nitrophenyl-4-(2-chlorobenzamido)benzenesulfonate (14m, IC50 3.17⯵Mâ¯at P2Y2R, and 1.67⯵Mâ¯at GPR17) exhibited dual antagonistic activity. Compound 14l was shown to act as an allosteric antagonist at both receptors. In addition, GPR17-selective antagonists were identified including 3-nitrophenyl 4-benzamidobenzenesulfonate (14a, IC50 3.20⯵M) and 3-nitrophenyl 4-(3-(trifluoromethyl)benzamido)benzenesulfonate (14f, IC50 3.88⯵M). The developed antagonists were selective versus other closely related P2Y receptors. They were found to possess high chemical and metabolic stability in human liver microsomes and therefore present good starting points for developing potent multi-target drugs with potential applications in inflammatory diseases.