There is an urgent need for the discovery of new antileishmanial drugs with a new mechanism of action. Type 2 NADH dehydrogenase from
Leishmania infantum (
LiNDH2) is an enzyme of the parasite’s respiratory system, which catalyzes the electron transfer from NADH
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There is an urgent need for the discovery of new antileishmanial drugs with a new mechanism of action. Type 2 NADH dehydrogenase from
Leishmania infantum (
LiNDH2) is an enzyme of the parasite’s respiratory system, which catalyzes the electron transfer from NADH to ubiquinone without coupled proton pumping. In previous studies of the related NADH: ubiquinone oxidoreductase crystal structure from
Saccharomyces cerevisiae, two ubiquinone-binding sites (UQ
I and UQ
II) were identified and shown to play an important role in the NDH-2-catalyzed oxidoreduction reaction. Based on the available structural data, we developed a three-dimensional structural model of
LiNDH2 using homology detection methods and performed an in silico virtual screening campaign to search for potential inhibitors targeting the
LiNDH2 ubiquinone-binding site 1—UQ
I. Selected compounds displaying favorable properties in the computational screening experiments were assayed for inhibitory activity in the structurally similar recombinant NDH-2 from
S. aureus and leishmanicidal activity was determined in the wild-type axenic amastigotes and promastigotes of
L. infantum. The identified compound, a
substituted
6-methoxy-quinalidine, showed promising nanomolar leishmanicidal activity on wild-type axenic promastigotes and amastigotes of
L. infantum and the potential for further development.
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