Abstract
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 (UQI and UQII) 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–UQI. 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.
Highlights
The leishmaniases, classified as neglected tropical diseases, comprise a group of diseases caused by more than 20 known species of protozoan Leishmania parasites that are usually transmitted to humansMolecules 2018, 23, 772; doi:10.3390/molecules23040772 www.mdpi.com/journal/moleculesMolecules 2018, 23, 772 through bites of infected female phlebotomine sandflies
Sequence identity is above the twilight zone [17], we find that further sequence analysis using primary sequence alignment methods might lead to more useful data, especially regarding amino acids’ similarity within the UQI
This indicates that the mechanism of binding for compound 15 as a general NDH-2 inhibitor is debatable, correct according to the binding hypothesis
Summary
The leishmaniases, classified as neglected tropical diseases, comprise a group of diseases caused by more than 20 known species of protozoan Leishmania parasites that are usually transmitted to humansMolecules 2018, 23, 772; doi:10.3390/molecules23040772 www.mdpi.com/journal/moleculesMolecules 2018, 23, 772 through bites of infected female phlebotomine sandflies. There are three main forms of leishmaniasis, described as cutaneous, visceral or kala-azar, and mucocutaneous. The enzyme family of type 2 NADH:quinone oxidoreductases (NDH-2s) is present in various microorganisms and plants, and a possible variation in humans [2,3]. These enzymes are putative drug targets for the treatment of parasitic infections such as leishmaniasis as these parasites present a NDH-2, LiNDH2 in L. infantum [4]. NDH-2 is a peripheral membrane protein which forms an intimate dimer, in which packing of the monomeric units within the dimer creates an amphiphilic membrane–anchor domain structure [5]
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