Designed multi-target ligand (DML) is an emerging strategy for the development of new drugs and involves the engagement of multiple targets with the same moiety. In the context of NSAIDs it has been suggested that targeting the thromboxane prostanoid (TP) receptor along with cyclooxygenase-2 (COX-2) may help to overcome cardiovascular (CVS) complications associated with COXIBs. In the present work, azaisoflavones were studied for their COX-2 and TP receptor binding activities using structure based drug design (SBDD) techniques. Flavonoids were selected as a starting point based on their known COX-2 inhibitory and TP receptor antagonist activity. Iterative design and docking studies resulted in the evolution of a new class scaffold replacing the benzopyran-4-one ring of flavonoids with quinolin-4-one. The docking and binding parameters of these new compounds are found to be promising in comparison to those of selective COX-2 inhibitors, such as SC-558 and celecoxib. Owing to the lack of structural information, a model for the TP receptor was generated using a threading base alignment method with loop optimization performed using an ab initio method. The model generated was validated against known antagonists for TP receptor using docking/MMGBSA. Finally, the molecules that were designed for selective COX-2 inhibition were docked into the active site of the TP receptor. Iterative structural modifications and docking on these molecules generated a series which displays optimum docking scores and binding interaction for both targets. Molecular dynamics studies on a known TP receptor antagonist and a designed molecule show that both molecules remain in contact with protein throughout the simulation and interact in similar binding modes.
Microbial communities on aerial plant leaves may contribute to the degradation of organic air pollutants such as phenol. Epiphytic
bacteria capable of phenol degradation were isolated from the leaves of green ash trees grown at a site rich in airborne pollutants.
Bacteria from these communities were subjected, in parallel, to serial enrichments with increasing concentrations of phenol
and to direct plating followed by a colony autoradiography screen in the presence of radiolabeled phenol. Ten isolates capable
of phenol mineralization were identified. Based on 16S rDNA sequence analysis, these isolates included members of the genera
Acinetobacter, Alcaligenes, and Rhodococcus. The sequences of the genes encoding the large subunit of a multicomponent phenol hydroxylase (mPH) in these isolates indicated
that the mPHs of the gram-negative isolates belonged to a single kinetic class, and that is one with a moderate affinity for
phenol; this affinity was consistent with the predicted phenol levels in the phyllosphere. PCR amplification of genes for
catechol 1,2-dioxygenase (C12O) and catechol 2,3-dioxygenase (C23O) in combination with a functional assay for C23O activity
provided evidence that the gram-negative strains had the C12O−, but not the C23O−, phenol catabolic pathway. Similarly, the
Rhodococcus isolates lacked C23O activity, although consensus primers to the C12O and C23O genes of Rhodococcus could not be identified. Collectively, these results demonstrate that these leaf surface communities contained several taxonomically
distinct phenol-degrading bacteria that exhibited diversity in their mPH genes but little diversity in the catabolic pathways
they employ for phenol degradation. 相似文献
Despite the vast surface area of terrestrial plant leaves and the large microbial communities they support, little is known of the ability of leaf-associated microorganisms to access and degrade airborne pollutants. Here, we examined bacterial acquisition and degradation of phenol on leaves by an introduced phenol degrader and by natural phyllosphere communities. Whole-cell gfp-based Pseudomonas fluorescens bioreporter cells detected phenol on leaves that had previously been transiently exposed to gaseous phenol, indicating that leaves accumulated phenol; moreover, they accumulated it in sites that were accessible to epiphytic bacteria and to concentrations that were at least 10-fold higher than those in the air. After inoculated leaves were exposed to gaseous 14C-phenol, leaves harbouring the phenol-degrading Pseudomonas sp. strain CF600 released eight times more 14CO2 than did leaves harbouring a non-degrading mutant, demonstrating that CF600 actively mineralized phenol on leaves. We evaluated phenol degradation by natural microbial communities on green ash leaves that were collected from a field site rich in airborne organic pollutants. We found that significantly more phenol was mineralized by these leaves when the communities were present than by these leaves following surface sterilization. Thus, phenol-degrading organisms were present in these natural communities and were metabolically capable of phenol degradation. Collectively, these results provide the first direct evidence that bacteria on leaves can degrade an organic pollutant from the air, and indicate that bacteria on leaves could potentially contribute to the natural attenuation of organic air pollutants. 相似文献
Plasmonics - An online web application was developed for the study of surface plasmon resonance (SPR) of different materials using angular and wavelength modulation. The present web application... 相似文献
