RESUMEN
ABSTRACT: Haemonchus contortus is among the most prevalent pathogenic gastrointestinal nematodes that poses significant health issues in small ruminants. Control of Haemonchus contortus relies on benzimidazoles. However, most small ruminants have started showing benzimidazole resistance due to prolonged and intensive drug consumption It is postulated that single nucleotide polymorphism of specific amino acids, Phe200Tyr, Phe167Tyr and Glu198Ala in ß-tubulin is the causal factor of this resistance. Hence, a plethora of alternative anthelmintic drug is currently being investigated. The present study intends to investigate in silico anthelmintic potential of glycyrrhetinic acid and thymol against wild and mutant ß-tubulin protein of Haemonchus contortus. Based on binding energies obtained in docking studies using AutoDock 4.0, mutant ß-tubulin at Phe200Tyr, Phe167Tyr and Glu198Ala illustrates insignificant changes in binding affinity of albendazole in comparison to the wild ß-tubulin. However, glycyrrhetinic acid and thymol exhibited significantly greater binding affinities towards mutant ß-tubulin in comparison to the albendazole-wild ß-tubulin binding affinity. Hence, these phytocompounds can potentially inhibit both wild and mutant Haemonchus contortus ß-tubulin polymerization. If established by in vitro and in vivo experiments, glycyrrhetinic acid could be an alternative anthelmintic compound, thus, further motivating the concept of reverse pharmacognosy. SUPPLEMENTARY INFORMATION: is available for this paper at 10.1007/s12639-020-01274-w.
RESUMEN
Understanding the influence of ubiquitously present plant steroids on mammalian cell biology is currently of interest. Feedback inhibition of HMGCoA reductase (HMGCR) catalytic activity in the transformation of HMG-CoA to mevalonate is a significant regulatory step in sterol biosynthetic pathway. To assess the role of dietary steroids in this biochemical transformation, the phytosteroid isoform 28-homobrassinolide (28-HB), 90 % pure, obtained from Godrej Agrovet (India) was used to determine its effect on mammalian HMG-CoA reductase. Photometric assay of pure human and select rat tissue HMGCR post 28-HB oral feed, PCR-HMGCR gene expression, and in silico docking of 28-HB and HMGCoA on HMGCR protein template were carried out. Using an oral feed regimen of pure 28-HB, we noted a decrease of 16 % in liver, 17.1 % in kidney and 9.3 % in testicular HMGCR enzyme activity, 25 % in HMGCR gene expression and 44 % in the activity of pure human HMGCR due to this plant oxysterol. In silico docking studies yielded binding metrics for 28-HB-HMGCR lower than for HMGCoA-HMGCR, indicating stronger binding of HMGCR by this ligand. 28-HB exerts differential effects on rat tissue HMGCR, down regulates liver HMGCR gene expression and significantly inhibits HMGCR activity.