PPIs are mainly metabolized by CYP2C19. It has a stereoselectivity effect on R- and S-isomers of PPIs according to previous studies. However, no study has been reported to elucidate the binding mechanism at the atomic level based on the CYP2C19 crystal structure. Recently, the advent of the first crystal structure of CYP2C19 allowed us to take in silico approaches including MD simulation, MM/GBSA calculation, energy decomposition, and alanine scanning to explore the stereoselectivity of CYP2C19 on R- and S-isomers of PPIs. The key residues responsible for the selective binding for R- and S-isomers of omeprazole, lansoprazole, and pantoprazole are disclosed by free energy and alanine scanning analysis. Structural analysis showed that chiral isomers of PPIs alter their conformations to have strong binding affinities with CYP2C19. Furthermore, a theoretical pharmacophore model of PPIs was obtained with the importance of pharmacophore feature being weighted, basing on our results. Our results are valuable for designing and synthesizing new generation of PPIs in the future.

Berberine is an isoquinoline alkaloid that has drawn extensive attention because it possesses various biological activities. Several mechanisms have been proposed to interpret the anticancer activity of berberine. However, these explanations are mostly based on its downstream-regulated genes or proteins; information on the direct target proteins that mediate the antiproliferative action of berberine remains unclear. In this study, a computational pipeline based on a ligand–protein inverse docking program and mining of the ‘Connectivity MAP’ data was adopted to explore the potential target proteins for berberine. The results showed that four proteins, that is calmodulin, cytochrome P450 3A4, sex hormone-binding globulin, and carbonic anhydrase II, were suggested to be the potential targets of berberine. The anticalmodulin property of berberine was demonstrated with an in vitro phosphodiesterase activity assay. Flow cytometric analysis found that G1 cell cycle arrest induced by berberine in Bel7402 cells was enhanced by cotreatment with calmodulin inhibitors. Western blotting results indicated that berberine treatment decreased phosphorylation of calmodulin kinase II and blocked subsequent MEK1 activation as well as p27 protein degradation. These results suggested that calmodulin might play crucial roles in berberine-induced cell cycle arrest in cancer cells.

The arginine derivative Fmoc-Arg^ω,ω′(Boc)₂-OH has been prepared in perfect yield starting from Fmoc-Orn·HCl and N,N′-di-Boc-N′′-triflyguanidine with the presence of diisopropylethylamine (DIEA). This work provides an efficient and economical method for the preparation of this compound.

The multi-target quantitative structure-activity relationship (QSAR) study of human immunodeficiency virus (HIV-1) inhibitors was addressed by applying a simple, yet effective linear regression model based on the multi-task learning paradigm. QSAR studies were performed on three datasets of HIV-1 inhibitors targeted on protease, integrase and reverse transcriptase, respectively. By using the multi-task learning method, the synergy among different set of inhibitors was exploited and an efficient multi-target QSAR modeling for HIV-1 inhibitors was obtained. The general descriptor features and drug-like features for compound description were ranked according to their jointly importance in multi-target QSAR modeling, respectively. A SAReport for investigating the relationships between compound structures and binding affinities was presented based on our multiple target analysis, which is expected to provide useful clues for the design of novel multi-target HIV-1 inhibitors with increasing likelihood of successful therapies.