Objetivos e Atividades
- culture the fungi Aspergillus, isolated from the marine environment, such as sponge or coral to obtain the hit compound and structurally related benzylpyrrolidines
- to create a virtual library of benzylpyrrolidines, fiscalins and xanthones with drug-like properties, applying computational filters, in order to select the molecules that comply with the Lipinski rule of five and other features described as important for efflux pumps inhibition
- carry out in silico screening of these libraries by docking studies against the 3D AcrAB-TolC and other microbial efflux pump structures and exclude potential efflux pump substrates and mammalian P-gp modulators [19]
- synthetize hit compounds that emerge from virtual screening based on the biomimetic starting materials and the group experience [5,20-23]
- study the effects of the new compounds for antimicrobial activity against multidrug-resistant pathogens and possible
Resultados Esperados/Atingidos
- isolate novel bioactive natural products
- synthesize libraries of highly potent smallmolecules based on the marine natural products and to establish SAR, hopefully with some as lead compounds having potent antimicrobial activity AND circumvent MDR. These expectations are based on the use of the crystallographic structure of bacterial efflux pumps in the docking studies. This synergistic discovery platform will be exploited in translational directions beyond the potentiation of conventional antimicrobial treatments including studies with aquaculture pathogens. This comprehensive step of design with drug-like properties will expedite the preclinical development of lead compound. It is also expected achieve optimized marine-natural compounds analogues with feasible synthesis and with reduced toxicity. One important repercussion of this project will be to apply to aquatic environments and have both industrial/pharmaceutical applications that will be further
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