Computer-aided drug design approaches applied to screen natural product's structural analogs targeting arginase in Leishmania spp

Abstract

Introduction: Leishmaniasis is a disease with high mortality rates and approximately 1.5 million new cases each year. Despite the new approaches and advances to fight the disease, there are no effective therapies. Methods: Hence, this study aims to screen for natural products' structural analogs as new drug candidates against leishmaniasis. We applied Computer-aided drug design (CADD) approaches, such as virtual screening, molecular docking, molecular dynamics simulation, molecular mechanics-generalized Born surface area (MM-GBSA) binding free estimation, and free energy perturbation (FEP) aiming to select structural analogs from natural products that have shown anti-leishmanial and anti-arginase activities and that could bind selectively against the Leishmania arginase enzyme. Results: The compounds 2H-1-benzopyran, 3,4-dihydro-2-(2-methylphenyl)-(9CI), echioidinin, and malvidin showed good results against arginase targets from three parasite species and negative results for potential toxicities. The echioidinin and malvidin ligands generated interactions in the active center at pH 2.0 conditions by MM-GBSA and FEP methods. Conclusions: This work suggests the potential anti-leishmanial activity of the compounds and thus can be further in vitro and in vivo experimentally validated.

Keywords: Leishmania arginase; antiprotozoal agents; drug discovery; computer-aided drug design; leishmaniasis; molecular dynamics simulation.

Figure 1.. Virtual screening of the compounds selected from the NuBBE database.

Binding affinities toward L. infatum and H. sapiens ARG targets were analyzed by linear regression and Pearson’s correlation coefficient. Solid orange line: linear regression; dotted orange lines: 95% confidence intervals. The solid green square was calculated using the maximum binding affinities of the 6 NPs (A). Normalized binding affinities heatmap of 25 selected compounds on L. infantum, L. mexicana, and L. braziliensis against their human homolog (B). Binary heatmap showing positive (red) or negative (blue) predicted toxicities (C). Chemical structure of ZINC39120134 (D), ZINC14807307 (E), and ZINC897714 (F).

Figure 2.. Structural conformation of ARG with its active site.

Colors blue and green represent the cartoon representation of pH 2.0 and pH 7.0. The red box shows the active site of ARG.

Figure 3.. RMSD, SASA, and RG analysis.

(A) RMSD is shown the conformational changes reported at pH 2.0. (B) SASA shows a greater solvent access surface area to ARG at pH 2.0 than at pH 7.0. (C) RG shows the same behavior as RMSD.

Figure 4.. Plots of MD simulation of each complex.

More significant conformational changes of ARG enzyme are shown at pH 2.0. (A) RMSD plot of ChainA concerning the whole protein. (B) RG analysis. (C) RMSF per residue of backbone.

Figure 5.. 2D representation of the last frame of each complex.

(A) Last frame at pH 2.0. and (B) Last frame at pH 7.0. Green represents the hydrophobic interaction between enzyme-ligand, color sky blue represents the hydrogen bond interaction.