RESUMEN
Plasmepsin II (PM II) is an attractive target for anti-malaria drug discovery, which involves in host hemoglobin degradation in the acidic food vacuole. In this study, we demonstrated the successful use of structure-based virtual screening to identify inhibitors of PM II from two chemical database. Five novel non-peptide inhibitors were identified and revealed moderate inhibitory potencies with IC50 ranged from 4.62 ± 0.39 to 9.47 ± 0.71 µM. The detailed analysis of binding modes using docking simulations for five inhibitors showed that the inhibitors could be stabilized by forming multiple hydrogen bonds with catalytic residues (Asp 34 and Asp 214) and also with other key residues.
Asunto(s)
Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Descubrimiento de Drogas , Inhibidores Enzimáticos/farmacología , Proteínas Protozoarias/antagonistas & inhibidores , Ácido Aspártico Endopeptidasas/metabolismo , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Modelos Moleculares , Estructura Molecular , Proteínas Protozoarias/metabolismo , Relación Estructura-ActividadRESUMEN
The discovery of novel tetrahydropyrrolo[1,2-c]pyrimidines derivatives from Bay41_4109 as hepatitis B virus (HBV) inhibitors is herein reported. The structure-activity relationship optimization led to one highly efficacious compound 28a (IC50 = 10 nM) with good PK profiles and the favorite L/P ratio. The hydrodynamic injection model in mice clearly demonstrated the efficacy of 28a against HBV replication.
RESUMEN
The study of iron chelators as cancer chemotherapeutic agents is still in its infancy. Accordingly, there is a need to optimize new chelating molecules for iron chelation therapy and cancer treatment. Previous studies have demonstrated that the ligand tris(1-pyrazolyl) borohydride and its derivates were able to chelate ferrous iron, but very little research focused on their biological properties and applications in cancer treatment. So, in this study, several boron-pyrazole derivatives were chosen for the examination of their effects on the proliferation of human hepatocellular carcinoma (HCC) cell lines. The results suggested that potassium tris(4-methyl-1-pyrazolyl) borohydride (KTp(4-Me)) exhibited the most potent anti-tumor activities among the candidates. Hence, the antiproliferative activity and the iron chelating capacity of the iron chelator KTp(4-Me) in HCC cell lines HepG2 and Hep3B were characterized. KTp(4-Me) could disrupt cell iron uptake and affect signaling pathways of iron regulation in HCC cell lines and induced the expression of TfR1 and HIF-1α in a concentration-dependent manner, which was a typical cell response to iron deficiency. Moreover, KTp(4-Me) arrested cell cycle in S phase and induced cell apoptosis in both Hep3B and HepG2 cells. Overall, our results provide a promising starting point and the possibility of the future development and applications of KTp(4-Me) in HCC therapy.
Asunto(s)
Antineoplásicos/farmacología , Compuestos de Boro/farmacología , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/tratamiento farmacológico , Pirazoles/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Compuestos de Boro/química , Compuestos de Boro/uso terapéutico , Ciclo Celular/efectos de los fármacos , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Células Hep G2 , Humanos , Estructura Molecular , Pirazoles/química , Pirazoles/uso terapéutico , Transducción de Señal/efectos de los fármacosRESUMEN
Malaria is one of the most devastating infectious diseases in the developing world. Until now, only one candidate malaria vaccine RTS,S/AS01 has shown modest protection in phase 3 trial in African infants. Hence the treatment of malaria still depends on the current chemotherapeutic drugs. Considering the resistance of malaria parasites to almost all used antimalarial drugs, aiming at multi-targets rather than a single target will be a more promising strategy. Previous studies have shown that myricetin and fisetin exhibited in vitro antimalarial activity against Plasmodium falciparum, but very little research focused on the molecular mechanism for their parasiticidal activity. The cysteine protease falcipain-2 and aspartic protease plasmepsin II have long been considered as important antimalarial drug targets, especially combined inhibition of these two proteases. In this study, we determined that myricetin and fisetin are dual inhibitors of falcipain-2 and plasmepsin II, which might account for their antimalarial properties. Overall, the dual inhibition of falcipain-2 and plasmepsin II by myricetin and fisetin has shed light on a possible mechanism for their antimalarial activity and provided a rationale for further development as antimalarial drugs.
Asunto(s)
Antimaláricos/farmacología , Ácido Aspártico Endopeptidasas/antagonistas & inhibidores , Inhibidores de Cisteína Proteinasa/farmacología , Flavonoides/farmacología , Plasmodium falciparum/efectos de los fármacos , Proteínas Protozoarias/antagonistas & inhibidores , Antimaláricos/química , Ácido Aspártico Endopeptidasas/metabolismo , Cisteína Endopeptidasas/metabolismo , Inhibidores de Cisteína Proteinasa/química , Flavonoides/química , Flavonoles , Humanos , Cinética , Simulación del Acoplamiento Molecular , Estructura Molecular , Plasmodium falciparum/enzimología , Proteínas Protozoarias/metabolismo , Proteínas RecombinantesRESUMEN
This study applied an efficient virtual screening strategy integrating molecular docking with MM-GBSA rescoring to identify diverse human dihydroorotate dehydrogenase (hDHODH) inhibitors. Eighteen compounds with IC(50) values ranging from 0.11 to 18.8 µM were identified as novel hDHODH inhibitors that exhibited overall species-selectivity over Plasmodium falciparum dihydroorotate dehydrogenase (pfDHODH). Compound 8, the most potent one, showed low micromolar inhibitory activity against hDHODH with an IC(50) value of 0.11 µM. Moreover, lipopolysaccharide-induced B-cell assay and mixed lymphocyte reaction assay revealed that most of the hits showed potent antiproliferative activity against B and T cells, which demonstrates their potential application as immunosuppressive agents. In particular, compound 18 exhibited potent B-cell inhibitory activity (IC(50) = 1.78 µM) and presents a B-cell-specific profile with 17- and 26-fold selectivities toward T and Jurkat cells, respectively.