Comparative study of structural models of Leishmania donovani and human GDP-mannose pyrophosphorylases

•GDP-mannose Pyrophosphorylase is crucial for the virulence and survival of the Leishmania parasite.•In the absence of an experimental structure, we propose models of this key enzyme for glycoconjugates biosynthesis.•Structural models were carefully refined by molecular dynamics simulations.•Docking of known inhibitors in the catalytic site allowed to rationalize their activity.•This study could facilitate developments of novel anti-leishmaniosis therapeutics.

Leishmania is the parasite responsible for the neglected disease leishmaniasis. Its virulence and survival require biosynthesis of glycoconjugates, whose guanosine diphospho-d-mannose pyrophosphorylase (GDP-MP) is a key player. However, experimentally resolved structures of this enzyme are still lacking. We herein propose structural models of the GDP-MP from human and Leishmania donovani. Based on a multiple sequences alignment, the models were built with MODELLER and then carefully refined with all atom molecular dynamics simulations in explicit solvent. Their quality was evaluated against several standard criteria, including their ability to bind GDP-mannose assessed by redocking calculations. Special attention was given in this study to interactions of the catalytic site residues with the enzyme substrate and competitive inhibitors, opening the perspective of medicinal chemistry developments.

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