Identification of novel inhibitors of S-adenosyl-L-homocysteine hydrolase via structure-based virtual screening and molecular dynamics simulations.

S-adenosyl-L-homocysteine hydrolase (SAHase) is an important regulator in the methylation reactions in many organisms and thus is crucial for numerous cellular functions. In recent years, SAHase has become one of the popular targets for drug design, and SAHase inhibitors have exhibited potent antiviral activity. In this study, we established the complex-based pharmacophore models based on the known crystal complex of SAHase (PDB ID: 1A7A) to screen the drug-likeness compounds of ChEMBL database. Then, three molecular docking programs were used to validate the reliability of compounds, involving Libdock, CDOCKER, and AutoDock Vina programs. The four promising hit compounds (CHEMBL420751, CHEMBL346387, CHEMBL1569958, and CHEMBL4206648) were performed molecular dynamics simulations and MM-PBSA calculations to evaluate their stability and binding-free energy in the binding site of SAHase. After screening and analyzing, the hit compounds CHEMBL420751 and CHEMBL346387 were suggested to further research to obtain novel potential SAHase inhibitors. A series of computer-aided drug design methods, including pharmacophore, molecular docking, molecular dynamics simulation and MM-PBSA calculations, were employed in this study to identity novel inhibitors of S-adenosyl-L-homocysteine hydrolase (SAHase). Some compounds from virtual screening could form various interactions with key residues of SAHase. Among them, compounds CHEMBL346387 and CHEMBL420751 exhibited potent binding affinity from molecular docking and MM-PBSA, and maintained good stability at the binding site during molecular dynamics simulations as well. All these results indicated that the selected compounds might have the potential to be novel SAHase inhibitors.

Synthesis and biological evaluation of novel pentanediamide derivatives as S-adenosyl-l-homocysteine hydrolase inhibitors.

A series of novel pentanediamide derivatives were designed, synthesized and evaluated as S-adenosyl-l-homocysteine hydrolase (SAHase) inhibitors in this study. Some compounds showed good inhibitory activity against SAHase. The optimal compound 7i showed good inhibitory activity against SAHase with IC50 value of 3.58 ± 0.19 µM, cytotoxicity with IC50 values ranging from 13.16 ± 1.44 to 21.23 ± 0.73 µM against four tumor cell lines (MCF-7, A549, MGC-803, Hela) and very weak cytotoxicity (IC50 = 84.22 ± 1.89 µM) on normal LO2 cells. In addition, compound 7i showed potency against respiratory syncytial virus with EC50 value of 27.4 µM and selectivity index of 6.84. Further molecular simulation study suggested that compound 7i had good ADMET properties, and strongly binds to the active site of SAHase. In summary, compound 7i could serve as a new lead compound for further screening novel non-adenosine SAHase inhibitors.

Discovery of novel N-aryl pyrrothine derivatives as bacterial RNA polymerase inhibitors.

Bacterial RNA polymerase (RNAP) is a validated drug target for broad-spectrum antibiotics, and its "switch region" is considered as the promising binding site for novel antibiotics. Based on the core scaffold of dithiolopyrrolone, a series of N-aryl pyrrothine derivatives was designed, synthesized, and evaluated for their antibacterial activity. Compounds generally displayed more active against Gram-positive bacteria, but less against Gram-negative bacteria. Among them, compound 6e exhibited moderate antibacterial activity against clinical isolates of rifampin-resistant Staphylococcus aureus with minimum inhibition concentration value of 1-2 µg/ml and inhibited Escherichia coli RNAP with IC50 value of 12.0 ± 0.9 µM. In addition, compound 6e showed certain degree of cytotoxicity against HepG2 and LO2 cells. Furthermore, molecular docking studies suggested that compound 6e might interact with the switch region of bacterial RNAP in a similar conformation to myxopyronin A. Together, the N-aryl pyrrothine scaffold is a promising lead for discovery of antibacterial drugs acting against bacterial RNAP.

Anti-Hepatitis B Virus Activity of Esculetin from Microsorium fortunei In Vitro and In Vivo.

Coumarins are widely present in a variety of plants and have a variety of pharmacological activities. In this study, we isolated a coumarin compound from Microsorium fortunei (Moore) Ching; the compound was identified as esculetin by hydrogen and carbon spectroscopy. Its anti-hepatitis B virus (HBV) activity was investigated in vitro and in vivo. In the human hepatocellular liver carcinoma 2.2.15 cell line (HepG2.2.15) transfected with HBV, esculetin effecting inhibited the expression of the HBV antigens and HBV DNA in vitro. Esculetin inhibited the expression of Hepatitis B virus X (HBx) protein in a dose-dependent manner. In the ducklings infected with duck hepatitis B virus (DHBV), the levels of DHBV DNA, duck hepatitis B surface antigen (DHBsAg), duck hepatitis B e-antigen (DHBeAg), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) decreased significantly after esculetin treatment. Summing up the above, the results suggest that esculetin efficiently inhibits HBV replication both in vitro and in vivo, which provides an opportunity for further development of esculetin as antiviral drug.

Synthesis and biological evaluation of novel SIPI-7623 derivatives as farnesoid X receptor (FXR) antagonists.

Most of reported steroidal FXR antagonists are restricted due to low potency. We described the design and synthesis of novel nonsteroidal scaffold SIPI-7623 derivatives as FXR antagonists. The most potent compound A-11 (IC50 = 7.8 ± 1.1 µM) showed better activity compared to SIPI-7623 (IC50 = 40.8 ± 1.7 µM) and guggulsterone (IC50 = 45.9 ± 1.1 µM). Docking of A-11 in FXR's ligand-binding domain was also studied.