Discovery of potential novel TRPC5 inhibitors by virtual screening and bioassay.

The transient receptor potential canonical channel 5 (TRPC5), a member of the TRPC family, plays a crucial role in the regulation of various physiological activities and diseases, including those related to the central nervous system, cardiovascular system, kidney, and cancer. As a nonselective cation channel, TRPC5 mainly controls the influx of extracellular Ca2+ into cells, thereby modulating cellular depolarization and intracellular ion concentration. Inhibition of TRPC5 by small molecules presents a promising approach for the treatment of TRPC5-associated diseases. In this study, we conducted a comprehensive virtual screening of more than 1.5 million molecules from the Chemdiv database (https://www.chemdiv.com) to identify potential inhibitors of hTRPC5, utilizing the published structures and binding sites of hTRPC5 as a basis. Lipinski's rule, Veber's rule, PAINS filters, pharmacophore analysis, molecular docking, ADMET evaluation and cluster analysis methods were applied for the screening. From this rigorous screening process, 18 candidates exhibiting higher affinities to hTRPC5 were subsequently evaluated for their inhibitory effects on Ca2+ influx using a fluorescence-based assay. Notably, two molecules, namely SML-1 and SML-13, demonstrated significant inhibition of intracellular Ca2+ levels in hTRPC5-overexpressing HEK 293T cells, with IC50 values of 10.2 µM and 10.3 µM, respectively. These findings highlight SML-1 and SML-13 as potential lead molecules for the development of therapeutics targeting hTRPC5 and its associated physiological activities and diseases.

neo-Clerodane Diterpenoids from the Aerial Parts of Scutellaria barbata with Anti-Inflammatory Activity.

The bioactivity-guided isolation on the Scutellaria barbata extract resulted in the purification of four undescribed neo-clerodane diterpenoids, scuttenlines A-D (1-4), alone with 20 known diterpenoids (5-24). The chemical structures of them were elaborated by extensive spectroscopic means, including 1D, 2D-NMR and HR-MS. The anti-inflammatory potential ability of 1-24 was screened in lipopolysaccharide-stimulated mouse RAW 264.7 cells. Scuttenline C (IC50 =1.9 µM) and 18 (IC50 =3.7 µM) exhibited potent activity to inhibit NO production.

Evaluation of the Shale Oil Reservoir and the Oil Enrichment Model for the First Member of the Lucaogou Formation, Western Jimusaer Depression, Junggar Basin, NW China.

The Lucaogou Formation (Fm) in the Jimusaer depression is the first large-scale development of a terrigenous clastic sedimentary shale oil reservoir in China. Nearly one billion tons of shale oil resources have been discovered. However, the current exploration and development is concentrated in the eastern part of the sag. The limited geological understanding in the western area has restricted the prediction and development of "sweet spots" for shale oil. To help rectify this, we have studied the petrology, geochemistry, oil content, and pore properties of the second part of the first member (Mbr) of the Lucaogou Fm (P2l1 2) in a typical well (Ji-X) in the western part of the sag. The results show that P2l1 2 in the Jimusaer sag is a mixed fine-grained sedimentary system composed of sandstone, mudstone, and carbonate, which can be divided into seven types: dolomitic mudstone, calcareous mudstone, mudstone, mixed fine-grained rock, argillaceous limestone, sandstone, and argillaceous dolomite. The organic matter type of P2l1 2 in well Ji-X is dominated by types I and II, and this is the best source rock in the whole exploration area of the Jimusaer sag. The overall oil saturation is relatively high, but the maturity of crude oil is low, and the overall oil quality is heavy, which is mainly controlled by the sedimentary environment and maturity of source rocks. Lithology and reservoir physical properties are the key to control oil content. The high-quality light oil reservoir lithology is argillaceous dolomite and sandstone. The higher the content of macropores and mesopores, the weaker the heterogeneity of the pore structure, and the better the oil content in the reservoir. There are four light oil sweet spots in the upper part (burial depth less than 4366 m), and there are excellent source rocks with high HI and high organic matter content near each sweet spot. This discovery of shale oil enrichment regularity will effectively guide the development of shale oil in continental lacustrine basins in other parts of the world.