Search

Background: The cyanoacrylate fungicide phenamacril targeting fungal myosin I has been widely used for controlling Fusarium head blight (FHB) of wheat caused by the pathogenic fungus Fusarium graminearum worldwide. Therefore, there is great interest in the discovery and development of novel FgMyo1 inhibitors through structure-based drug design for the treatment of FHB. Results: In this study, the binding mechanism of phenamacril with the FgMyo1 was predicted by an integrated molecular modeling strategy. The predicted key phenamacril-binding residues of FgMyo1 were further experimentally validated by point mutagenesis and phenamacril sensitivity assessment. Four novel key residues responsible for phenamacril binding were identified, highlighting the reliability of the theoretical predictions. The subsequent optimization of phenamacril derivatives led to the discovery of a novel compound 10, which shows better activity than phenamacril against conidial germination of F. graminearum, but not against other fungal species. Moreover, 10 also inhibits conidial germination of phenamacril-resistant strains effectively. Further experiments illustrated that application of compound 10 could dramatically inhibit deoxynivalenol (DON) biosynthesis. Conclusion: Overall, our results further optimize and develop the binding model of phenamacril-myosin I. Furthermore, compound 10 was found and has the potential to be developed as a species-specific fungicide for management of FHB. This article is protected by copyright. All rights reserved.

Binding of different ligands to glucocorticoid receptor (GR) may induce different conformational changes and even trigger completely opposite biological functions. To understand the allosteric communication within the GR ligand binding domain, the folding pathway of helix 12 (H12) induced by the binding of the agonist dexamethasone (DEX), antagonist RU486, and modulator AZD9567 are explored by molecular dynamics simulations and Markov state model analysis. The ligands can regulate the volume of the activation function‐2 through the residues Phe737 and Gln738. Without ligand or with agonist binding, H12 swings from inward to outward to visit different folding positions. However, the binding of RU486 or AZD9567 perturbs the structural state, and the passive antagonist state appears more stable. Structure‐based virtual screening and in vitro bioassays are used to discover novel GR ligands that bias the conformation equilibria toward the passive antagonist state. HP‐19 exhibits the best anti‐inflammatory activity (IC50 = 0.041 ± 0.011 µm) in nuclear factor‐kappa B signaling pathway, which is comparable to that of DEX. HP‐19 also does not induce adverse effect‐related transactivation functions of GR. The novel ligands discovered here may serve as promising starting points for the development of GR modulators., The glucocorticoid receptor (GR) ligand binding domain structural ensemble is characterized by the molecular dynamics (MD) simulations and Markov state model analysis. Based on the GR antagonist conformations sampled by MD simulations, virtual screening and in vitro bioassays are performed. Six novel GR ligands with anti‐inflammatory activities are discovered. HP‐19 is a promising candidate for the development of GR modulators.

Lung cancer is a leading cause of cancer-related death worldwide. Cyanopyridines and aminocyanopyridines with carbon-nitrogen bonds have been proved to exert significant anticancer, antibacterial, and anti-inflammatory effects. In this study, we showed that aminocyanopyridine 3o and 3k displaying potent antitumor activity via inhibiting the signal transducer and activator of transcription 3 (STAT3) pathway. They blocked the constitutive STAT3 phosphorylation in a dose- and time-dependent manner and regulated the transcription of STAT3 target genes encoding apoptosis factors. Most importantly, 3o also inhibited interleukin-6-induced STAT3 activation and nuclear localization. Furthermore, 3o significantly inhibited the tumor growth of H460-derived xenografts. Taken together, these findings suggest that 3o and 3k are promising therapeutic drug candidates for lung cancer by inhibiting persistent STAT3 signaling.

A series of tetrahydrobenzothieno[2,3-d]pyrimidine derivatives were designed, synthesized, and evaluated as inhibitors of FGFR1. These analogs were synthesized via Gewald's reaction under mild conditions. The structures of the synthesized compounds were characterized by spectroscopic data (IR, (1) H NMR and MS). Their antitumor activities were evaluated against H460, A549 and U251 cell lines in vitro. Results revealed that the tested compounds showed moderate antitumor activities. Structure-activity relationship analyses indicated that compounds with an aromatic ring substituted in the C-2 position or with larger molecules such as 3g, 4c, and 7 were more effective than others. The compound, 3g (78.8% FGFR1 inhibition at 10 μm), was identified to have the most potent antitumor activities, with IC50 values of 7.7, 18.9, and 13.3 μm against the H460, A549, and U251 cell lines, respectively. Together, the results suggested that tetrahydrobenzothieno[2,3-d]pyrimidine derivatives may serve as a potential agent for the treatment of FGFR1-mediated cancers.