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In silico studies of aminated thioxanthones: bacterial multidrug efflux pumps vs P-glycoprotein
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1  Laboratório de Química Orgânica e Farmacêutica, Departamento de Ciências Químicas, Faculdade de Farmácia, Universidade do Porto, Portugal
2  Centro Interdisciplinar de Investigação Marinha e Ambiental (CIIMAR), Universidade do Porto, Portugal

Published: 31 October 2018 by MDPI in 4th International Electronic Conference on Medicinal Chemistry session ECMC-4

Currently, one of the most urgent threats is antimicrobial resistance, which leads to the inefficacy of drugs in therapeutics, and can arise from several reasons, being the overexpression of efflux pumps one of them. These pumps are ubiquitous in bacteria, and their overexpression allows bacteria to develop multidrug resistance, through the extrusion of antimicrobial drugs. They can be divided into five families, being the resistance-nodulation-division (RND) family and the major facilitator superfamily (MFS) the most relevant. Efforts have been put towards a selective, efficient efflux pump inhibitor (EPI), and although some progress has been achieved, in the therapeutic scenario no EPIs have been approved.1

Our group has experience in molecular docking and synthesis of aminated thioxanthones with modulatory activity in the mammal efflux pump P-glycoprotein (P-gp), which is also useful in the detoxification of xenobiotics.2,3 Taking this into account, the aim of this work was the design of a virtual library of approximately 1.000 aminated (thio)xanthones, the performance of docking studies in bacterial efflux pumps whose crystal structure has been elucidated and available in the Protein Data Bank and in a model of the human P-gp. For the docking studies bacterial efflux pumps chosen were both from the RND family: AcrB, from the AcrAB-TolC efflux system,4 and MexB, from the MexAB-OprM efflux system.5

The compounds that will be selected for synthesis are the ones that virtually displayed good scores for the bacterial referred efflux pumps and lower scores for P-gp, since this would mean that, in vivo, these compounds would efficiently reduce antimicrobial resistance while not interfering with human detoxification pathways.

Acknowledgements: This research was developed under Project No. POCI-01-0145-FEDER-028736, co-financed by COMPETE 2020, Portugal 2020 and the European Union through the ERDF, and by FCT through national funds.


  1. Durães, F.; Pinto, M.; Sousa, E., Medicinal Chemistry Updates on Bacterial Efflux Pump Modulators. Curr Med Chem 2018, Feb 9. doi: 10.2174/0929867325666180209142612.
  2. Palmeira, A.; Vasconcelos, M. H.; Paiva, A.; Fernandes, M. X.; Pinto, M.; Sousa, E., Dual inhibitors of P-glycoprotein and tumor cell growth: (re)discovering thioxanthones. Biochem Pharmacol 2012, 83 (1), 57-68.
  3. Palmeira, A.; Rodrigues, F.; Sousa, E.; Pinto, M.; Vasconcelos, M. H.; Fernandes, M. X., New uses for old drugs: pharmacophore-based screening for the discovery of P-glycoprotein inhibitors. Chem Biol Drug Des 2011, 78 (1), 57-72.
  4. Yu, E. W.; Aires, J. R.; McDermott, G.; Nikaido, H., A periplasmic drug-binding site of the AcrB multidrug efflux pump: a crystallographic and site-directed mutagenesis study. J Bacteriol 2005, 187 (19), 6804-15.
  5. Sennhauser, G.; Bukowska, M. A.; Briand, C.; Grutter, M. G., Crystal structure of the multidrug exporter MexB from Pseudomonas aeruginosa. Journal of molecular biology 2009, 389 (1), 134-45.
Keywords: thioxanthones; docking; bacterial efflux pumps; P-glycoprotein