Computational Studies of Drug Repurposing Targeting P-Glycoprotein-Mediated Multidrug-Resistance Phenotypes in Agents of Neglected Tropical Diseases

Abstract

Mammalian ABCB1 P-glycoprotein is an ATP-dependent efflux pump with broad substrate specificity associated with cellular drug resistance. Homologous to this role in mammalian biology, the P-glycoprotein of agents of neglected tropical diseases (NTDs) mediates the emergence of multidrug-resistance phenotypes. The clinical and socioeconomic implications of NTDs are exacerbated by the lack of research interest among Big Pharma for treating such conditions. This work aims to characterise P-gp homologues in certain agents of key NTDs, namely (1) Protozoa: Leishmania major, Trypanosoma cruzi; (2) Helminths: Onchocerca volvulus, Schistosoma mansoni. Based on structural modelling of the organismal P-gp homologues, potential antibiotics targeting these structures were identified based on similarity and repurposing of existing drugs. Docking studies of the Pgp receptor-antibiotic ligand complexes were carried out and the most tenable target-ligand conformations assessed. The interacting residues were identified, and binding pockets studied. The in silico studies yielded measurements of the relative efficacy of the new drugs, which need experimental validation. Our studies could lay the foundation for the development of effective synergistic or new therapies against key neglected tropical diseases. The potential mechanisms of multidrug resistance emergence in E. coli were examined.

Biological potential of eight medicinal plants collected in the restored landscape after mining in South Kalimantan

“…Existing antibiotic therapies have been seriously challenged by the spread of multidrug-resistant organisms [92]. For example, the emergence of multidrug-resistant S. aureus and C. albicans poses the greatest threat [93]. Since plants contain diverse bioactive phytochemicals with proven medicinal properties, exploring antimicrobial molecules of plant origin has gained attention [94].…”