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The Novel Serine/Threonine Protein Kinase LmjF.22.0810 from Leishmania major may be Involved in the Resistance to Drugs such as Paromomycin.
- Source :
-
Biomolecules [Biomolecules] 2019 Nov 11; Vol. 9 (11). Date of Electronic Publication: 2019 Nov 11. - Publication Year :
- 2019
-
Abstract
- The identification and clarification of the mechanisms of action of drugs used against leishmaniasis may improve their administration regimens and prevent the development of resistant strains. Herein, for the first time, we describe the structure of the putatively essential Ser/Thr kinase LmjF.22.0810 from Leishmania major . Molecular dynamics simulations were performed to assess the stability of the kinase model. The analysis of its sequence and structure revealed two druggable sites on the protein. Furthermore, in silico docking of small molecules showed that aminoglycosides preferentially bind to the phosphorylation site of the protein. Given that transgenic LmjF.22.0810-overexpressing parasites displayed less sensitivity to aminoglycosides such as paromomycin, our predicted models support the idea that the mechanism of drug resistance observed in those transgenic parasites is the tight binding of such compounds to LmjF.22.0810 associated with its overexpression. These results may be helpful to understand the complex machinery of drug response in Leishmania .<br />Competing Interests: The authors declare no conflict of interest.
- Subjects :
- Antiprotozoal Agents
Drug Resistance genetics
Humans
Leishmania major enzymology
Leishmania major pathogenicity
Leishmaniasis, Cutaneous genetics
Leishmaniasis, Cutaneous parasitology
Molecular Dynamics Simulation
Paromomycin chemistry
Protein Serine-Threonine Kinases chemistry
Leishmania major drug effects
Leishmaniasis, Cutaneous drug therapy
Paromomycin adverse effects
Protein Serine-Threonine Kinases genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2218-273X
- Volume :
- 9
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Biomolecules
- Publication Type :
- Academic Journal
- Accession number :
- 31718000
- Full Text :
- https://doi.org/10.3390/biom9110723