Natural compounds from plants controlling leishmanial growth via DNA damage and inhibiting trypanothione reductase and trypanothione synthetase: an in vitro and in silico approach.

In the present study, four different natural compounds including quercetin, gallic acid, rutin, and lupeol were studied for their anti-leishmanial potentials with anticipated mechanism of action through in vitro and in silico approaches. Results showed that rutin was exceedingly active (IC; 91.2 µg/ml) against the promastigote form of compared to quercetin (IC; 182.3 µg/ml), gallic acid (IC; 198.00 µg/ml) and lupeol (IC; 200.77 µg/ml). Similarly, rutin was highly active against the amastigote form as well, followed by quercetin, gallic acid and lupeol with IC values of 101.3 µg/ml, 137.4 µg/ml, 277.2 µg/ml, and 298.9 µg/ml, respectively. These compounds were found to be nontoxic to human blood erythrocytes even at the highest concentration (1000 µg/ml) tested. Rutin and lupeol showed promising DNA degradation/fragmentation activity against the DNA of treated promastigotes which increased with the increase in concentration of the compounds. The in silico investigation revealed that these ligands have high affinity with the important catalytic residues of trypanothione reductase (Try-R) where, rutin showed the lowest docking score (i.e., - 6.191) followed by lupeol (- 5.799), gallic acid and quercetin. In case of ligands' interaction with trypanothione synthetase (Try-S), rutin again showed highest interaction with docking score of - 6.601 followed by quercetin (- 4.996), lupeol and gallic acid. The ADMET prediction of these compounds showed that all the parameters were within the acceptable range as defined for human use while molecular dynamics simulation supported the good interaction of quercetin and rutin against both enzymes. These findings suggest that the studied compounds may control leishmanial growth via DNA damage and inhibiting Try-R and Try-S, the two unique but critical enzymes for leishmania growth.