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

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.

Keywords: Leishmania; anti-target; arginase; cytochrome P450; flavonoid; in silico; leishmaniasis; natural products; pregnane-X-receptor; screen; sulfotransferase.

Figure 1

Schematic representation of the EIIP/AQVN criterion for selection of candidate Leishmania arginase inhibitors. Extended active group (orange): AQVN (3.13–3.58), EIIP (0.09–0.134). Core active group domain (red): AQVN (3.25–3.42), EIIP (0.12–0.134). Chemical space (blue) AQVN (2.40–3.30) EIIP (0.000–0.116) EIIP/AQVN domain of homologous distribution of >90% compounds from the PubChem Compound Database [30]. Statistics: Extended active group—inside the active wider domain: 21 (87.5%), outside the active wider domain: 3 (12.5%); Core active group—inside the active domain: 12 (50%), outside the active domain: 12 (50%).

Figure 2

PLS coefficients in the Leishmania arginase inhibitors’ QSAR model.

Figure 3

Basic skeleton of known Leishmania arginase inhibitors from the ChEMBL database. R1, R3 = OH, OAc; R2 = OAc or hexopyranose ring (see Table S6).

Figure 4

(a) The most active compound (CHEMBL3109443); and (b) the least active compound (CHEMBL3109440) in the Leishmania arginase model with PLS variables. Green dots: TIP probes, yellow dots: DRY probes, blue dots: N1, red dots: O probes. Lines that connect dots are variables, such as DRY—DRY, TIP—TIP, N1—TIP etc.

Figure 5

PLS scores of 200 candidates in the Leishmania arginase 3D QSAR model. Red: candidates, black: 18 Leishmania arginase inhibitors.

Figure 6

The binding site of Leishmania arginase in the homology model, with the most important residues for interaction listed.

Figure 7

Docking position of best candidate, compound 39 (Table 2) in the binding site of Leishmania arginase homology model with marked intermolecular interactions. Green lines: hydrogen bonds, purple: aromatic/hydrophobic interactions

Figure 8

Interaction matrix between proposed ligands and Anti-targets. Color code: black = 1.0; grey = 0.5, white = 0.0. Columns: A: Glide XP PXR, B: Glide XP SULT, C: Glide XP CYP 2a6, D: Glide XP CYP 2c9, E: Glide XP CYP 3a4, F: Glide XP Total, G: Autodock 4 PXR, H: Autodock 4 SULT, I: Autodock 4 CYP 2a6, J: Autodock 4 CYP 2c9, K: Autodock 4 CYP 3a4, L: Autodock 4 Total, M: Vina PXR, N: Vina SULT, O: Vina CYP 2a6, P: Vina CYP 2c9, Q: Vina CYP 3a4, R: Vina Total, S: Grand Total.