In vitro evaluation of antileishmanial activity of computationally screened compounds against Ascorbate Peroxidase: Combating Amphotericin B drug resistance [PublishAheadOfPrint]

In Visceral Leishmaniasis (VL), the host macrophages generate oxidative stress to destroy the pathogen, while Leishmania combat the harmful effect of radicals by redox homeostasis through its unique trypanothione cascade. L. donovani Ascorbate Peroxidase (LdAPx) is a redox enzyme that regulates trypanothione cascade and detoxify the effect of H₂O₂. Absence of LdAPx homologue in human makes it an excellent drug target. In this study, the homology model of LdAPx was built including heme and diverse compounds were prefiltered (PAINS, ADMET and Lipinski's 5) thereafter screened against the LdAPx model. Compounds having good affinity in terms of Glide XP score were clustered to select diverse compounds for experimental validation. A total of 26 cluster representatives were procured and tested on promastigotes culture yielding 12 compounds with good antileishmanial activity. Out of them six compounds were safer on the BALB/c peritoneal macrophages and were also effective on disease causing intracellular amastigotes. Three out of six compounds inhibited recombinant LdAPx in non-competitive manner and also demonstrated partial reversion of resistant property in AmB resistant strain that may be due to increased level of ROS and decrease of GSH content. However, inhibition of LdAPx in resistant parasite enhanced annexin V staining, activation of metacaspase-like proteases activity which may help in DNA fragmentation and apoptotic like cell death.

Thus, the present study will help in search for specific hits and templates of potential therapeutic interest and therefore may facilitate the development of new drugs for combination therapy against VL.

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