A point cloud-based deep learning strategy for protein-ligand binding affinity prediction.

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.

Superlithiation Performance of Pyridinium Polymerized Ionic Liquids with Fast Li+ Diffusion Kinetics as Anode Materials for Lithium-Ion Battery.

Polymerized ionic liquids (PILs) with super ion diffusion kinetics have aroused considerable attention in rechargeable batteries, which are very promising to solve the problem of the slow ion diffusion kinetics in organic electrode materials. Theoretically, PILs incorporated redox groups are very suitable as anode materials to realize "superlithiation" performance, achieving high lithium storage capacity. In this study, redox pyridinium-based PILs (PILs-Py-400) have been synthesized through trimerization reactions by pyridinium ionic liquids with cyano groups under an appropriate temperature (400 °C). The positively charged skeleton, extended conjugated system, abundant micropores, and amorphous structure for PILs-Py-400 can boost the utilization efficiency of redox sites. A high capacity of 1643 mAh g-1 at 0.1 A g-1 (96.7% of the theoretical capacity) has been obtained, indicating intriguing 13 Li+ redox reactions in per repeating unit of one pyridinium ring, one triazine ring, and one methylene. Moreover, PILs-Py-400 exhibit excellent cycling stability with a capacity of around 1100 mAh g-1 at 1.0 A g-1 after 500 cycles, and the capacity retention is 92.2%.

Degradation of mirubactin to multiple siderophores with varying Fe(III) chelation properties.

Three siderophores mirubactins B-D (4-6) were identified as the degradation products of previously isolated mirubactin (1). Their structures were revealed by HR-ESI-MS/MS, NMR analyses, and density functional calculations, among which 4 contains an unusual cyclic amidine functionality. Cyclic voltammetry showed that 5 and 6 have reduced iron complexing capacity. Mirubactin (1) and Fe(III) could also form a stable complex, which may be an ingenious approach to compete for iron acquisition by the producing organisms.

Characterization of Chalkophomycin, a Copper(II) Metallophore with an Unprecedented Molecular Architecture.

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.

Genome mining of novel rubiginones from Streptomyces sp. CB02414 and characterization of the post-PKS modification steps in rubiginone biosynthesis.

BACKGROUND: Rubiginones belong to the angucycline family of aromatic polyketides, and they have been shown to potentiate the vincristine (VCR)-induced cytotoxicity against VCR-resistant cancer cell lines. However, the biosynthetic gene clusters (BGCs) and biosynthetic pathways for rubiginones have not been reported yet. RESULTS: In this study, based on bioinformatics analysis of the genome of Streptomyces sp. CB02414, we predicted the functions of the two type II polyketide synthases (PKSs) BGCs. The rub gene cluster was predicted to encode metabolites of the angucycline family. Scale-up fermentation of the CB02414 wild-type strain led to the discovery of eight rubiginones, including five new ones (rubiginones J, K, L, M, and N). Rubiginone J was proposed to be the final product of the rub gene cluster, which features extensive oxidation on the A-ring of the angucycline skeleton. Based on the production profiles of the CB02414 wild-type and the mutant strains, we proposed a biosynthetic pathway for the rubiginones in CB02414. CONCLUSIONS: A genome mining strategy enabled the efficient discovery of new rubiginones from Streptomyces sp. CB02414. Based on the isolated biosynthetic intermediates, a plausible biosynthetic pathway for the rubiginones was proposed. Our research lays the foundation for further studies on the mechanism of the cytochrome P450-catalyzed oxidation of angucyclines and for the generation of novel angucyclines using combinatorial biosynthesis strategies.

Discovery of a DNA Topoisomerase I Inhibitor Huanglongmycin N and Its Congeners from Streptomyces sp. CB09001.

Huanglongmycin (HLM) congeners G-N (7-14) were isolated from Streptomyces sp. CB09001. Among them, 10-12 possesses a tricyclic scaffold with benzene-fused pyran/pyrone, confirmed by X-ray single crystal diffraction analysis of 12. The structure-activity relationship study of 1, 13, and 14 revealed not only the stronger cytotoxicity of 14 against tested cancer cells but also the critical role of the C-7 ethyl group of 14 in its binding to the DNA-topoisomerase I complex.

Superlithiation Performance of Covalent Triazine Frameworks as Anodes in Lithium-Ion Batteries.

Organics with the merit of renewability have been viewed as the promising alternative of inorganic electrode materials in lithium-ion batteries, but most of them display inferior performance due to the sluggish ion/electron diffusion and the potential dissolution in aprotic electrolytes. Here, covalent triazine frameworks (CTFs-1), full of vertical pores and layered spaces for Li+ transfer, have been synthesized with p-dicyanobenzene as the monomer by a facile two-step method including a prepolymerization with CF3SO3H as the catalyst and deep polymerization in molten ZnCl2. CTFs-1-400, obtained at the deep polymerization temperature of 400 °C, exhibits the superlithiation property with the specific capacities of 1626 mA h g-1 at 25 °C and 1913 mA h g-1 at 45 °C at 100 mA g-1, indicating the formation of Li6C6/Li6C3N3 in the reduction process. Electrochemical analysis and density functional theory calculation indicate that the ultrahigh capacity is mainly contributed by the capacitance of micropores and the redox capacity of benzene and triazine rings. Moreover, CTFs-1-400 displays the specific capacity of 740 mA h g-1 for 1000 cycles at 1 A g-1 with almost no capacity fading.

Bioactive α-Pyrone Derivatives from the Endophytic Fungus Diaporthe sp. CB10100 as Inducible Nitric Oxide Synthase Inhibitors.

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.

ANO6 promotes cell proliferation and invasion in glioma through regulating the ERK signaling pathway.

PURPOSE: Anoctamin6 (ANO6) plays a crucial role in several cancers, whereas the specific role of ANO6 in glioblastoma is unclear. METHODS: Kaplan-Meier survival analysis was used to analysis the correlation between ANO6 and survival rate of patients with glioblastoma. Univariate Cox regression analysis was used to analysis the correlation among ANO6 expression level,and age, gender, WHO and overall survival rate. Immunohistocemical technique, RT-PCR and western blot were used to dected the ANO6 expression. CCK8, colony formation and transwell were used to detected cell viability, cell proliferation and cell invasion in glioblastoma cells transfected with sh-ANO6 and ANO6 overexpression. In addition, after SHG-44 cells trasfected with ANO6 overexpression were ERK inhibitor (PD98059), CCK8, colony formation and transwell were used to detected cell viability, cell proliferation and cell invasion. Western blot was used to detected ERK protein level and the phosphorylation level of ERK in T89G and U87MG cells tranfected wih sh-ANO6. RESULTS: The results indicated that the ANO6 expression level was significantly associated with patients' age and tumor stage. Univariate Cox regression analysis showed that the ANO6 expression level, age, gender and tumor stage were not related to the overall survival rate. ANO6 inhibition significantly suppressed the viability, invasion and the ability of colony formation in glioma cells, while ANO6 overexpression led to the opposite results in SHG-44 cells. ANO6 knockdown strongly inhibits the phosphorylation level and nuclear translocation of extracellular signal-regulated kinase (ERK) protein to inhibit ERK signaling. ERK inhibitor significantly decreased the cell proliferation and invasion in SHG-44 cells transfected with sh-ANO6. CONCLUSION: This study revealed that ANO6 activited ERK signaling pathway through promoting the nuclear translocation of ERK to increase the proliferation and invasion of glioblastoma cells.