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.

Comparison of outcomes following three surgical techniques for patients with severe jejunoileal atresia.

BACKGROUND: Severe jejunoileal atresia is associated with prolonged parenteral nutrition, higher mortality and secondary surgery. However, the ideal surgical management of this condition remains controversial. This study aimed to compare the outcomes of patients with severe jejunoileal atresia treated by three different procedures. METHODS: From January 2007 to December 2016, 105 neonates with severe jejunoileal atresia were retrospectively reviewed. Of these, 42 patients (40.0%) underwent the Bishop-Koop procedure (BK group), 49 (46.7%) underwent primary anastomosis (PA group) and 14 (13.3%) underwent Mikulicz double-barreled ileostomy (DB group). Demographics, treatment and outcomes including mortality, morbidity and nutrition status were reviewed and were compared among the three groups. RESULTS: The total mortality rate was 6.7%, showing no statistical difference among the three groups (P = 0.164). The BK group had the lowest post-operative complication rate (33.3% vs 65.3% for the PA group and 71.4% for the DB group, P = 0.003) and re-operation rate (4.8% vs 38.8% for the PA group and 14.3% for the DB group, P < 0.001). Compared with the BK group, the PA group showed a positive correlation with the complication rate and re-operation rate, with an odds ratio of 4.15 [95% confidence interval (CI): 1.57, 10.96] and 12.78 (95% CI: 2.58, 63.29), respectively. The DB group showed a positive correlation with the complication rate when compared with the BK group, with an odds ratio of 7.73 (95% CI: 1.67, 35.72). The weight-for-age Z-score at stoma closure was -1.22 (95% CI: -1.91, -0.54) in the BK group and -2.84 (95% CI: -4.28, -1.40) in the DB group (P = 0.039). CONCLUSIONS: The Bishop-Koop procedure for severe jejunoileal atresia had a low complication rate and re-operation rate, and the nutrition status at stoma closure was superior to double-barreled enterostomy. The Bishop-Koop procedure seems to be an appropriate choice for severe jejunoileal atresia.

Tuning zinc coordination architectures by benzenedicarboxylate position isomers and bis(triazole).

Three position isomers 1,2-, 1,3-, 1,4-benzenedicarboxylate and 1,4-bis(1,2,4-triazol-4-yl)benzene were used to assembly zinc(II) coordination polymers {[Zn2(btx)0.5(1,2-bdc)2(H2O)]·H2O}n (1), {[Zn(btx)(1,3-bdc)]·2H2O·(DMF)}n (2) and {[Zn(btx)(1,4-bdc)]·3H2O}n (3). 1 is a (3,4,4,4)-connected two-dimensional network with point symbol (4(2)·6)(4(4)·6(2))(4(3)·6(2)·8)(4(2)·6·10(3)). 2 shows a two-dimensional (4,4) network. 3 exhibits a 5-fold interpenetrated three-dimensional diamondoid network. The structural versatility shows that the structures of coordination polymers can be tuned by the position isomers ligands. The luminescence and thermal stability were investigated.

A polythreading array formed by a (3,5)-connected 3D anionic network and 1D cationic chains: synthesis, structure, and catalytic properties.

An unusual copper(II) coordination polymer {[Cu(tmtz)(H2O)4][Cu2(tmtz)2(sip)2]·4H2O}n (1) (tmtz = 1,4-bis(1,2,4-triazol-1-ylmethyl)-2,3,4,5-tetramethylbenzene, sip = 5-sulfoisophthalate) is synthesized by the hydrothermal reaction. X-Ray structural analysis shows that 1 is comprised of two distinct and crystallographically independent polymeric motifs polythreading together. The first motif of 1 is an unusual (3,5)-connected 3D anionic network [Cu2(tmtz)2(sip)2]. The second motif in 1 is the [Cu(tmtz)(H2O)4]n 1D cationic chain. A polythreading array formed by a (3,5)-connected 3D anionic network and 1D cationic chains. The catalytic performance exhibits that 1 is active as a catalyst for the degradation of methyl orange. The thermal analysis is also observed.

[Validity and reliability of the Chinese version of Pediatric Quality of Life Inventory Version 3.0 Asthma Modul].

OBJECTIVE: To evaluate the reliability and validity of parent proxyreport scales of Pediatric Quality of Life Inventory Version 3.0 (PedsQLTM) Asthma Module (Chinese version). METHODS: Two hundred and thirty-three asthmatic children and their parents from the Children's Hospital of Chongqing Medical University were enrolled. Health related quality of life was assessed using the above mentioned PedsQLTM Asthma Module. The internal consistency was assessed using Cronbach's α coefficient, while its validity was tested through correlation analysis and exploratory factor analysis. RESULTS: The internal consistency reliability for Total Scale Summary Score (Cronbach's α=0.86), Asthma Score (Cronbach's α=0.80), Treatment Score (Cronbach's α=0.78), Worry Score (Cronbach's α=0.89) and Communication Score (Cronbach's α=0.93) were excellent. Seven major factors were extracted by factor analysis which basically matched the designed structure of the original version accounting for nearly 66% of the variance. Moderate to high correlations between items and the subscales were found, and the correlation coefficients ranged from 0.41 to 0.92(P<0.01). CONCLUSIONS: The reliability and validity of the parent proxy-report scales of PedsQLTM 3.0 Asthma Module of the Chinese version are as good as the original version.

A novel two-dimensional nickel(II) coordination polymer with 1,4-bis(1,2,4-triazol-1-ylmethyl)benzene and azide ligands.

The coordination geometry of the Ni(II) atom in the title complex, poly[diazidobis[mu-1,4-bis(1,2,4-triazol-1-ylmethyl)benzene-kappa(2)N(4):N(4')]nickel(II)], [Ni(N(3))(2)(C(12)H(12)N(6))(2)](n), is a distorted octahedron, in which the Ni(II) atom lies on an inversion centre and is coordinated by four N atoms from the triazole rings of two symmetry-related pairs of 1,4-bis(1,2,4-triazol-1-ylmethyl)benzene (bbtz) ligands and two N atoms from two symmetry-related monodentate azide ligands. The Ni(II) atoms are bridged by four bbtz ligands to form a two-dimensional (4,4)-network.

A novel three-dimensional cadmium(II) coordination polymer incorporating 1,4-bis(1,2,4-triazol-1-ylmethyl)benzene and thiocyanate.

In the title complex, poly[cadmiumII-mu2-1,4-bis(1,2,4-triazol-1-ylmethyl)benzene-di-mu2-thiocyanato], [Cd(NCS)2(C12H12N6)]n, the CdII atom lies on an inversion centre in a distorted octahedral environment. Four N atoms from the thiocyanate and 1,4-bis(1,2,4-triazol-1-ylmethyl)benzene (bbtz) ligands occupy the equatorial positions, and two S atoms from symmetry-related thiocyanate ligands occupy the axial positions. The benzene ring of the bbtz ligand lies about an inversion centre. Single thiocyanate bridges link the CdII atoms into two-dimensional sheets containing novel 16-membered [Cd4(mu-NCS-N:S)4] rings. The bbtz ligands further link these two-dimensional sheets into an unprecedented covalent three-dimensional network for the cadmium-thiocyanate system.

A novel three-dimensional copper(II) coordination polymer with 1,4-bis(1,2,4-triazol-1-ylmethyl)benzene and thiocyanate.

In the title complex, poly[copper(II)-di-2-thiocyanato-2-1,4-bis(1,2,4-triazol-1-ylmethyl)benzene], [Cu(NCS)2(C12H12N6)]n, the CuII atom lies on an inversion centre in a tetragonally distorted octahedral environment. Four N atoms from thiocyanate and 1,4-bis(1,2,4-triazol-1-ylmethyl)benzene (bbtz) ligands fill the equatorial positions, and S atoms from symmetry-related thiocyanate ligands fill the axial positions. The benzene ring of the bbtz ligand lies about an inversion centre. Single thiocyanate bridges link the CuII atoms into two-dimensional sheets containing an unprecedented 16-membered [Cu4(-NCS-N:S)4] ring. The bbtz ligands further link the two-dimensional sheets into a three-dimensional network.

A novel two-dimensional cobalt(II) coordination polymer with 1,4-bis(1,2,4-triazol-1-ylmethyl)benzene.

In the crystal structure of the title complex, poly[[diazidocobalt(II)]-di-mu-1,4-bis(1,2,4-triazol-1-ylmethyl)benzene-kappa(4)N(4):N(4')], [Co(N(3))(2)(bbtz)(2)](n), where bbtz is 1,4-bis(1,2,4-triazol-1-ylmethyl)benzene (C(12)H(12)N(6)), the Co(II) atom, which lies on an inversion centre, is six-coordinated by four N atoms from four bbtz ligands and by two N atoms from two azide ligands, in a distorted octahedral coordination environment. The Co(II) atoms are bridged by four bbtz ligands to form a two-dimensional [4,4]-network.