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Molecular modeling and molecular dynamics simulations of GPI 14 in Leishmania major: insight into the catalytic site for active site directed drug design. (English) Zbl 1412.92179
Summary: Leishmania major causes cutaneous form of leishmaniasis affecting 21 million people in developing countries. Overuse of the chemotherapeutics against leishmaniasis has resulted in the development of drug resistance in the parasite. To surmount this emerging threat we have attempted to target the surface molecules. Glycosylphosphatidylinositol is one such molecule that is present abundantly and thus our work revolves around the enzyme mannosyltransferase (GPI 14), an enzyme essential to add mannose on the glycosylphosphatidyl. It has been targeted for drug discovery on account of growing resistance to miltefosine in L. major. This paper serves as the first attempt to detect GPI 14 gene in L. major supported with modeling and molecular dynamic analysis of complete three dimensional structure of GPI 14. The functional analysis revealed multiple transmembrane regions in GPI 14 and a close phylogenetic relation with Trypanosoma species and Schistosoma mansoni with highest bootstrap values. The protein model obtained was subjected to minimization for 14 ns simulation. Eight derivatives of $$N$$-4-(-5(trifluoromethyl)-1-methyl-1$$H$$-benzo[$$d$$]imidazole-2-yl)phenyl) were docked onto GPI 14. The contact frequency of GPI 14 with the docked compounds suggested the inhibition of mannosylation proposing the druggability for leishmaniasis therapy.
##### MSC:
 92C60 Medical epidemiology 92C40 Biochemistry, molecular biology
##### Software:
AutoDock Vina; Gromacs; LINCS; MrBayes; PyMOL; Q-SiteFinder; SETTLE
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