In Silico Insights into the Mechanism of Action of Epoxy-α-Lapachone and Epoxymethyl-Lawsone in Leishmania spp

Abstract

Epoxy-α-lapachone (Lap) and Epoxymethyl-lawsone (Law) are oxiranes derived from Lapachol and have been shown to be promising drugs for Leishmaniases treatment. Although, it is known the action spectrum of both compounds affect the Leishmania spp. multiplication, there are gaps in the molecular binding details of target enzymes related to the parasite's physiology. Molecular docking assays simulations were performed using DockThor server to predict the preferred orientation of both compounds to form stable complexes with key enzymes of metabolic pathway, electron transport chain, and lipids metabolism of Leishmania spp. This study showed the hit rates of both compounds interacting with lanosterol C-14 demethylase (-8.4 kcal/mol to -7.4 kcal/mol), cytochrome c (-10.2 kcal/mol to -8.8 kcal/mol), and glyceraldehyde-3-phosphate dehydrogenase (-8.5 kcal/mol to -7.5 kcal/mol) according to Leishmania spp. and assessed compounds. The set of molecular evidence reinforces the potential of both compounds as multi-target drugs for interrupt the network interactions between parasite enzymes, which can lead to a better efficacy of drugs for the treatment of leishmaniases.

Keywords: Leishmania spp.; epoxy-α-lapachone; epoxymethyl-lawsone; leishmaniases; molecular docking.

Figure 1

Structural formulas of naphthoquinone and its derivatives. (A) Buparvaquone (3-[(4-tert-butylcyclohexyl)methyl]-4-hydroxynaphthalene-1,2-dione); (B) B6 (2-phenoxy-1,4-naphthoquinone); (C) β-lapachone (2H-Naphtho[1,2-b]pyran-5,6-dione,3,4-dihydro-2,2-dimethyl); (D) Epoxy-α-lapachone (2,2-Dimethyl-3,4-dihydro-spiro[2H-naphtho[2,3-b]pyran-10,2′-oxirane]-5(10H)-one); and (E) Epoxymethyl-lawsone (2-Methyl-4H-spiro-[naphthalene-1,20-oxiran]-4-one).

Figure 2

Molecular interaction of naphthoquinone derivatives with Leishmania spp. lanosterol C-14 demethylase. Docking assays were performed with (A) Lanosterol C-14 demethylase of Coccidioides posadasii; (B) L. (L.) amazonensis; (C) L. (V.) braziliensis. The 2D representation indicates the types of bonds that occur in Lanosterol C-14 demethylase with β-lapachone (2H-Naphtho[1,2-b]pyran-5,6-dione,3,4-dihydro-2,2-dimethyl-β-Lap), Epoxy-α-lapachone (2,2-dimethyl-3,4-dihydrospiro[benzo[g]chromene-10,20-oxiran]-5(2H)-one-Lap), and Epoxymethyl-lawsone (2-Methyl-4H-spiro-[naphthalene-1,20-oxiran]-4-one-Law).

Figure 3

Molecular interaction of naphthoquinone derivatives with Leishmania spp. cytochrome c. Docking assays were performed with cytochrome c of L. (L.) major (A); L. (L.) amazonensis (B); and L. (V.) braziliensis (C). The 2D representation indicates the types of bonds that occur in cytochrome c with Buparvaquone (3-[(4-tert-butylcyclohexyl)methyl]-4-hydroxynaphthalene-1,2-dione-BH), Epoxy-α-lapachone (2,2-dimethyl-3,4-dihydrospiro[benzo[g]chromene-10,20-oxiran]-5(2H)-one-Lap), and Epoxymethyl-lawsone (2-Methyl-4H-spiro-[naphthalene-1,20-oxiran]-4-one-Law).

Figure 4

Molecular interaction of naphthoquinone derivatives with Leishmania spp. glyceraldehyde 3-phosphate dehydrogenase. Docking assays were performed with glyceraldehyde 3-phosphate dehydrogenase of T. brucei (A); L. (L.) amazonensis (B); and L. (V.) braziliensis (C). The 2D representation indicates the types of bonds that occur in glyceraldehyde 3-phosphate dehydrogenase with 2-phenoxy-1,4-naphthoquinone (B6), Epoxy-α-lapachone (2,2-dimethyl-3,4-dihydrospiro[benzo[g]chromene-10,20-oxiran]-5(2H)-one-Lap), and Epoxymethyl-lawsone (2-Methyl-4H-spiro-[naphthalene-1,20-oxiran]-4-one-Law).