3CLpro inhibitors: DEL-based molecular generation.

Molecular generation (MG) via machine learning (ML) has speeded drug structural optimization, especially for targets with a large amount of reported bioactivity data. However, molecular generation for structural optimization is often powerless for new targets. DNA-encoded library (DEL) can generate systematic, target-specific activity data, including novel targets with few or unknown activity data. Therefore, this study aims to overcome the limitation of molecular generation in the structural optimization for the new target. Firstly, we generated molecules using the structure-affinity data (2.96 million samples) for 3C-like protease (3CLpro) from our own-built DEL platform to get rid of using public databases (e.g., CHEMBL and ZINC). Subsequently, to analyze the effect of transfer learning on the positive rate of the molecule generation model, molecular docking and affinity model based on DEL data were applied to explore the enhanced impact of transfer learning on molecule generation. In addition, the generated molecules are subjected to multiple filtering, including physicochemical properties, drug-like properties, and pharmacophore evaluation, molecular docking to determine the molecules for further study and verified by molecular dynamics simulation.

Very-High-Cycle Fatigue Behavior of Inconel 718 Alloy Fabricated by Selective Laser Melting at Elevated Temperature.

This study investigates the very-high-cycle fatigue (VHCF) behavior at elevated temperature (650 °C) of the Inconel 718 alloy fabricated by selective laser melting (SLM). The results are compared with those of the wrought alloy. Large columnar grain with a cellular structure in the grain interior and Laves/δ phases precipitated along the grain boundaries were exhibited in the SLM alloy, while fine equiaxed grains were present in the wrought alloy. The elevated temperature had a minor effect on the fatigue resistance in the regime below 108 cycles for the SLM alloy but significantly reduced the fatigue strength in the VHCF regime above 108 cycles. Both the SLM and wrought specimens exhibited similar fatigue resistance in the fatigue life regime of fewer than 107-108 cycles at elevated temperature, and the surface initiation mechanism was dominant in both alloys. In a VHCF regime above 107-108 cycles at elevated temperature, the wrought material exhibited slightly better fatigue resistance than the SLM alloy. All fatigue cracks are initiated from the internal defects or the microstructure discontinuities. The precipitation of Laves and δ phases is examined after fatigue tests at high temperatures, and the effect of microstructure on the formation and the propagation of the microstructural small cracks is also discussed.

Synthesis of phostones via DABCO-catalyzed bromocyclization of alkenylphosphonic acid monoesters.

The bromocyclization of 4-aryl-3-butenylphosphonic acid monoesters could proceed smoothly and rapidly in CH3CN with 1.2 equiv. of NBS in the presence of 0.02 equiv. of DABCO at room temperature, giving exclusively the six-membered ring bromophostones with high endo regioselectivity but poor diastereoselectivity. The diastereomers were separated and their relative configurations were determined based on their NMR analysis and X-ray crystallography. Furthermore, we preliminarily demonstrated that the asymmetric bromocyclization of these kinds of substrates was possible.

Subchronic toxicity study of ulvan from Ulva pertusa (Chlorophyta) in Wistar rats.

Ulvan extracted from Ulva pertusa (Chlorophyta) is a group of sulfated heteropolysaccharide, for simplicity, the sulfated polysaccharide is referred to as ulvan in this paper. To our knowledge, there is no detailed report investigating the toxicity of ulvan. In this study, the subchronic (6 months) toxicity of varying levels of ulvan extracted from U. pertusa was investigated in Wistar rats after oral administration. ALT, ALB, ALP, WBC, PLT, and liver relative organ weigh of female rats showed significantly difference at 3000 mg/kg body weight per day, compared with control group. On the other hand, TG, T-CHO concentrations of female rats (6 months) were significantly decreased at 600, 1200 and 3000 mg/kg body weight per day. This result proved that ulvan had antihyperlipidemic activity. Beside, ulvan showed anticoagulant activity in this study. Overall, our findings indicated that ulvan had affected specific hematology, serum biochemistry parameters and liver, and had great differences between males and females rats.