Arginase Flavonoid Anti-Leishmanial in Silico Inhibitors Flagged against Anti-Targets.

Sanja Glisic,Milan Sencanski,Strahinja Stevanovic,Alfonso García-Sosa,Vladimir Perovic

doi:10.3390/molecules21050589

Sanja Glisic, Milan Sencanski + Show 3 more

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https://doi.org/10.3390/molecules21050589

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Abstract

Arginase, a drug target for the treatment of leishmaniasis, is involved in the biosynthesis of polyamines. Flavonoids are interesting natural compounds found in many foods and some of them may inhibit this enzyme. The MetIDB database containing 5667 compounds was screened using an EIIP/AQVN filter and 3D QSAR to find the most promising candidate compounds. In addition, these top hits were screened in silico versus human arginase and an anti-target battery consisting of cytochromes P450 2a6, 2c9, 3a4, sulfotransferase, and the pregnane-X-receptor in order to flag their possible interactions with these proteins involved in the metabolism of substances. The resulting compounds may have promise to be further developed for the treatment of leishmaniasis.

Highlights

Leishmaniasis, a vector-borne infectious disease, is endemic in 98 countries in parts of the tropics, subtropics, and in Europe [1,2,3]
The virtual screening (VS) protocol in this paper was based on the application of sequential filters to select candidate anti-leishmanial arginase inhibitors
It was shown for targets in different infectious diseases (HIV, Ebola virus, malaria, bacterial infections) that small molecules with similar average quasi valence number (AQVN) and electron-ion interaction potential (EIIP) values interact with the common therapeutic target [24,25,26]

Summary

Introduction

Leishmaniasis, a vector-borne infectious disease, is endemic in 98 countries in parts of the tropics, subtropics, and in Europe [1,2,3]. Leishmaniasis can have skin, mucocutaneous, and visceral presentations caused by 20 different Leishmania parasite species. This is a neglected tropical disease (NTD) and a major public health problem that currently affects 12 million people with estimated 0.2 to. 0.4 million of new visceral leishmaniasis cases and 0.7 to 1.2 million of new cutaneous leishmaniasis cases each year, globally [1,4]. It is a severe co-infection with human immunodeficiency virus infection (HIV), where there is a high chance of developing the full-blown clinical disease with high relapse and mortality rates [5]. Arginase is the first enzyme involved in PA biosynthesis and hydrolyses arginine into ornithine and urea [7]

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