Metals play essential roles in life
by coordination with small
molecules, proteins, and nucleic acids. Although the coordination
of copper ions in many proteins and methanobactins is known, the coordination
chemistry of Cu(II) in natural products and their biological functions
remain underexplored. Herein, we report the discovery of a Cu(II)-binding
natural product, chalkophomycin (CHM, 1), from Streptomyces sp. CB00271, featuring an asymmetric square-coordination
system of a bidentate diazeniumdiolate and a conjugated 1H-pyrrole 1-oxide-oxazoline. The structure of 1 may inspire
the synthesis of Cu(II) chelators against neurodegenerative diseases
or Cu(II)-based antitumor therapeutics.
There is great interest to develop artificial intelligence-based protein–ligand binding affinity models due to their immense applications in drug discovery. In this paper, PointNet and PointTransformer, two pointwise multi-layer perceptrons have been applied for protein–ligand binding affinity prediction for the first time. Three-dimensional point clouds could be rapidly generated from PDBbind-2016 with 3772 and 11 327 individual point clouds derived from the refined or/and general sets, respectively. These point clouds (the refined or the extended set) were used to train PointNet or PointTransformer, resulting in protein–ligand binding affinity prediction models with Pearson correlation coefficients R = 0.795 or 0.833 from the extended data set, respectively, based on the CASF-2016 benchmark test. The analysis of parameters suggests that the two deep learning models were capable to learn many interactions between proteins and their ligands, and some key atoms for the interactions could be visualized. The protein–ligand interaction features learned by PointTransformer could be further adapted for the XGBoost-based machine learning algorithm, resulting in prediction models with an average Rp of 0.827, which is on par with state-of-the-art machine learning models. These results suggest that the point clouds derived from PDBbind data sets are useful to evaluate the performance of 3D point clouds-centered deep learning algorithms, which could learn atomic features of protein–ligand interactions from natural evolution or medicinal chemistry and thus have wide applications in chemistry and biology.
Inducible nitric oxide synthase (iNOS) produces NO from l-arginine and plays critical roles in inflammation and immune activation. Selective and potent iNOS inhibitors may be potentially used in many indications, such as rheumatoid arthritis, pain, and neurodegeration. In the current study, five new compounds, including a dibenzo-α- pyrone derivative ellagic acid B (5) and four α-pyrones diaporpyrone A–D (9–12), together with three known compounds (6–8), were isolated from the endophytic fungus Diaporthe sp. CB10100. The structures of these new natural products were unambiguously elucidated using NMR, HRESIMS or electronic circular dichroism calculations. Ellagic acid B (5) features a tetracyclic 6/6/6/6 ring system with a fused 2H-chromene, which is different from ellagic acid (4) with a fused 2H-chromen-2-one. Both 2-hydroxy-alternariol (6) and alternariol (7) reduced the expression of iNOS at protein levels in a dose-dependent manner, using a lipopolysaccharide (LPS)-induced RAW264.7 cell models. Also, they decreased the protein expression levels of pro-inflammatory cytokines, such as tumor necrosis factor-α, interleukin-6 and monocyte chemotactic protein 1. Importantly, 6 and 7 significantly reduced the production of NO as low as 10 μM in LPS-induced RAW264.7 cells. Molecular docking of 6 and 7 to iNOS further suggests that both of them may interact with iNOS. Our study suggests that 6 and 7, as well as the alternariol scaffold may be further developed as potential iNOS inhibitors.
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