The Prediction of LptA and LptC Protein-Protein Interactions and Virtual Screening for Potential Inhibitors.

Antibiotic resistance in Gram-negative bacteria remains one of the most pressing challenges to global public health. Blocking the transportation of lipopolysaccharides (LPS), a crucial component of the outer membrane of Gram-negative bacteria, is considered a promising strategy for drug discovery. In the transportation process of LPS, two components of the LPS transport (Lpt) complex, LptA and LptC, are responsible for shuttling LPS across the periplasm to the outer membrane, highlighting their potential as targets for antibacterial drug development. In the current study, a protein-protein interaction (PPI) model of LptA and LptC was constructed, and a molecular screening strategy was employed to search a protein-protein interaction compound library. The screening results indicated that compound 18593 exhibits favorable binding free energy with LptA and LptC. In comparison with the molecular dynamics (MD) simulations on currently known inhibitors, compound 18593 shows more stable target binding ability at the same level. The current study suggests that compound 18593 may exhibit an inhibitory effect on the LPS transport process, making it a promising hit compound for further research.

Discovery of 2,4-diphenyl-substituted thiazole derivatives as PRMT1 inhibitors and investigation of their anti-cervical cancer effects.

Cervical cancer is one of the most common cancers that affects middle-aged women and the discovery of new drugs to aid clinical management is needed. As an important member of the protein arginine methyltransferases (PRMTs) family, PRMT1 catalyzes the methylation of protein arginine, which can influence multiple biological processes of cancer cells, such as activating epithelial-mesenchymal transformation (EMT) and acquiring resistance to apoptosis. Therefore, PRMT1 can be considered as a potential drug target for cervical cancer. In the current study, a new sub-binding pocket was discovered by molecular modeling, and by introducing a third substitute on the thiazole group to occupy this pocket, a series of compounds were designed and synthesized as potential PRMT1 inhibitors. Of these, two compounds (ZJG51 and ZJG58) exhibited significant inhibitory activities against PRMT1 without significantly inhibiting PRMT5. Both ZJG51 and ZJG58 displayed potent inhibitory effects on the proliferation of four cancer-derived cell lines and ZJG51 exerted relative selectivity against the cervical cancer cell line, HeLa. Further studies showed that ZJG51 inhibited migration and induce the apoptosis of HeLa cells. Mechanistically, ZJG51 significantly regulated PRMT1 related proteins, and indicated that the induction of apoptosis and inhibition of migration by ZJG51 may involve the activation of Caspase 9 and the inhibition of EMT, respectively. Molecular dynamic simulation and free energy calculation showed that ZJG51 can bind to PRMT1 stably and the binding mode was predicted. These data indicated that introducing the third substitute on the five-membered ring could be a future direction for structure-based optimization of PRMT1 inhibitors, and ZJG51 could be an important lead compound to inform the design of more potent inhibitors.

Innovative method for the enrichment of high-polarity bioactive molecules present at low concentrations in complex matrices.

Ginsenoside Rg1 is a valuable bioactive molecule but its high polarity and low concentration in complex mixtures makes it a challenge to separate Ginsenoside Rg1 from other saponins with similar structures, resulting in low extraction efficiency. The successful development of effective Rg1 molecularly imprinted polymers that exhibit high selectivity and adsorption may offer an improved method for the enrichment of active compounds. In this work, molecularly imprinted polymers were prepared with two different methods, precipitation polymerization or surface imprinted polymerization. Comparison of the adsorption abilities showed higher adsorption of the surface molecularly imprinted polymers prepared by surface imprinted polymerization, 46.80 mg/g, compared to the 27.74 mg/g observed for the molecularly imprinted polymers prepared by precipitation polymerization. Therefore, for higher adsorption of the highly polar Rg1, surface imprinted polymerization is a superior technique to make Rg1 molecularly imprinted polymers. The prepared surface molecularly imprinted polymers were tested as a solid-phase extraction column to directionally enrich Rg1 and its analogues from ginseng tea and total ginseng extracts. The column with surface molecularly imprinted polymers showed higher enrichment efficiency and better selectivity than a C18 solid-phase extraction column. Overall, a new, innovative method was developed to efficiently enrich high-polarity bioactive molecules present at low concentrations in complex matrices.

Cytotoxic sesquiterpenes and lignans from Saussurea deltoidea.

Two new sesquiterpenes deltoiden A (1) and deltoiden B (2), and two new lignans deltoignan A (9) and deltoignan B (10), together with 14 known compounds, including six sesquiterpenes 3-8 and three lignans 11-13, were isolated from the whole plant of Saussurea deltoidea. Compounds 3-8 and 11-17 were isolated for the first time from this plant. Their structures were established by spectroscopic analysis, including 2D-NMR spectroscopic techniques. Cytotoxicities of compounds 1-13 were tested against three cancer cell lines A549, Hela and SMMC-7721. Results showed that 5, 6 and 7 exhibited cytotoxicity against SMMC-7721 with the IC(50) values of 6.49, 9.53, 1.23 µg/ml, 5 and 7 against A549 with the IC(50) values of 4.99 and 5.35 µg/ml, 5, 6, 7, 13 against Hela with the IC(50) values of 1.40, 4.75, 0.93 and 5.42 µg/ml, respectively. The structure-activity relationships of sesquiterpenes 1-8 were discussed on the base of cytotoxic results.

[Isoprenoids and phenylpropanoids from Saussurea deltoidea].

To investigate the chemical constituents of Saussurea deltoidea, 10 compounds were isolated from the title plant by various chromatography methods such as silica gel, RP-18 silica gel, Sephadex LH-20 column chromatography, HPLC, et al. Their structures were elucidated by spectral analysis. Five isoprenoids and Five phenylpropanoids were isolated and elucidated as (3R, 6R, 7E) -3-hydroxy-4, 7-megastigmadien-9-one (1), (3S, 5R, 6S, 7E) -5, 6-epoxy-3-hydroxy-7-megastigmen-9-one (2), 3-hydroxy-beta-damascone (3), S-(+) -dehydrovomifoliol (4), megastigman-5-ene-3beta, 9R-diol (5), coniferaldehyde (6), beta-hydroxypropiovanillone (7), 3-hydroxy-1-(4-hydroxy-3, 5-dimethoxyphenyl) -1-propanone (8), dihydrosyringenin (9), 4-[(1S) -3-hydroxy-1-methoxypropyl]-2, 6-dimenthoxyphenol (10). All the compounds were isolated from S. deltoidea for the first time.

3D QSAR studies on ketoamides of human cathepsin K inhibitors based on two different alignment methods.

Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were performed on 64 ketoamides as human cathepsin K (CatK) inhibitors, using ROCS ligand-based alignment and receptor-based alignment. Results generated from the ligand-based model were found to be superior to those obtained by the receptor-based model. CoMFA and CoMSIA field distributions are in good agreement with the structural characteristics of the binding groove of CatK, suggesting moderate substitutes at the P1, P2, P3 and P1' may favor the inhibitory activity of ketoamides. These results provide useful information in understanding the structural and chemical features of CatK in designing and finding novel potential CatK inhibitors as osteoporosis therapeutic agents.

[Studies on chemical constituents in fruit of Alpinia oxyphylla].

OBJECTIVE: To study the chemical constituents in fruit of Alpinia oxyphylla and their cytotoxicities on cancer cell lines. METHOD: Compounds were isolated and purified by various column chromatographic methods. Their structures were determined by physico-chemical properties and spectral analyses. Compound cytotoxicity was assessed by the sulforhodamine B (SRB) assay. RESULT: Eight compounds were obtained from Me2CO-H2O (70%) extract of the fruit of A. oxyphylla and their structures were identified as: (9E)-humulene-2, 3; 6, 7-diepoxide (1), 3(12), 7(13), 9(E)-humulatriene-2, 6-diol (2), (-)-oplopanone (3), yakuchinone A (4), yakuchinone B (5), tectochrysin (6), isovanillin (7), (2E, 4E)-6-hydroxy-2, 6-dimethylhepta-2, 4-dienal (8), and the cytotoxicities of compounds 1, 3-5 on cancer cell lines, A549, HT-29 and SGC-7901, were also investigated. CONCLUSION: Compounds 1-3, 7, 8 were isolated for the first time from this genus and compounds 1, 3-5 exhibited no cytotoxicity against three cancer cell lines at a concentration of 10 mg x L(-1).

Apoptosis inducement of bigelovin from Inula helianthus-aquatica on human Leukemia U937 cells.

Inula helianthus-aquatica C. Y. Wu is a traditional medicinal plant used to treat some cancers in folk herbal medicine of Yunnan, China. Bigelovin, a sesquiterpene lactone isolated from this herb, potently inhibits the growth of a panel of eight cancer cell lines, especially in human monoblastic leukemia U937 cells with an IC(50) value of 0.47 microM. Characteristic morphological features of apoptosis were observed in U937 cells treated with bigelovin. Annexin V and nuclear DNA content distribution assays showed that the percentage of Annexin V positive cells increased to 8.86% (24 h) with 1 microM bigelovin treatment, and cells treated with bigelovin at this concentration apparently arrested at G(0)/G(1) phase compared with the control. These data suggested that cytotoxic effect of bigelovin on U937 cells involves induction of apoptosis, and the cell cycle is arrested at G(0)/G(1) phase.

Natural inhibitors of DNA topoisomerase I with cytotoxicities.

DNA Topoisomerase I can cause DNA breaks and play a key role during cell proliferation and differentiation. It is an important target for anticancer agents. While screening for anticancer compounds, seven natural compounds, 1-7, showed potent cytotoxicities against a panel of ten cancer cell lines. Moreover, an inhibition assay demonstrated that they are also DNA topoisomerase I inhibitors, in which inhibitors 1-5 are new ones.

3D-QSAR study of sulfonamide inhibitors of human carbonic anhydrase II.

3D-QSAR models of Comparative of Molecular Field Analysis (CoMFA) and Comparative of Molecular Similarity Indices Analysis (CoMSIA) of 61 potent carbonic anhydrase II (CAII) sulfonamide inhibitors were performed using two methods. The conventional ligand-based 3D-QSAR studies were performed based on the lower energy conformations employing database alignment rule. The receptor-based 3D-QSAR models were also derived using bioactive conformations obtained by docking compounds to the active sites of CAII. The receptor-based model gave q(2) values of 0.623 and 0.562, r(2) values of 0.986 and 0.987 for CoMFA and CoMSIA, respectively, which were much better than those of ligand-based model (q(2) values of 0.532 and 0.466). The predictive ability of the models was validated using the test set of 10 compounds that were not included in the training set of 51 compounds. Results of CoMFA and CoMSIA suggested that heterocyclic sulfonamides are more active than aromatic sulfonamides, in the latter 1,3,5-triazole group substituting one hydrogen atom of the amido is favored and moderate groups in its 4- and 6-position are required. These results provided further understanding of the relationship between the structural features of CAII and its activities, which should be applicable to design and find new potential CAII inhibitors.

3D-QSAR and docking studies of aldehyde inhibitors of human cathepsin K.

In order to better understand the structural and chemical features of human cathepsin K (CatK), which is an important cysteine protease in the pathogenesis of osteoporosis, the 3D-QSAR (CoMFA) studies were conducted on recently explored aldehyde compounds with known CatK inhibitory activities. The genetic algorithm of GOLD2.2 has been employed to position 59 aldehyde compounds into the active sites of CatK to determine the probable binding conformation. Good correlations between the predicted binding free energies and the experimental inhibitory activities suggested that the identified binding conformations of these potential inhibitors are reliable. The docking results also provided a reliable conformational alignment scheme for 3D-QSAR model. Based on the docking conformations, highly predictive comparative molecular field analysis (CoMFA) was performed with q2 value of 0.723. The predictive ability was validated by some compounds that were not included in the training set. Furthermore, the CoMFA model was mapped back to the binding sites of CatK, to get a better understanding of vital interactions between the aldehyde compounds and the protease. The CoMFA field distributions are in good agreement with the structural characteristics of the binding groove of the CatK, which suggested that the n-Bu in R4 position is the favor group substitute at P1 and moderate groups in R2 group are required on P2 substitute. In addition, 3D-QSAR results also demonstrated that aldehyde is an important pharmacophore because of electrostatic effect. These results, together with the good correlations between the inhibitory activities and the binding free energies predicted by GOLD2.2, demonstrated the power of combining docking/QSAR approach to explore the probable binding conformations of compounds at the active sites of the protein target, and further provided useful information in understanding the structural and chemical features of CatK in designing and finding new potential inhibitors.