In silico Prediction and Pharmacokinetic Studies on Glucosinolates as a Potential Drug and Key Inhibitor Molecule for Lanosterol-14α- demethylase: A Fungal Membrane Biosynthesis Enzyme.

Background: Glucosinolates (β-thioglucoside-N-hydroxysulfates) are a water-soluble organic anion with sulfur- and nitrogen-containing glycosides which are found in abundance in Cruciferous plants. Ergosterol (ERG13) lanosterol-14α-demethylase protein has been targeted for inhibition studies as a key regulator enzyme of fungal membrane biosynthesis.

Objectives: To understand the molecular mechanism of inhibition of Ergosterol (ERG13) lanosterol- 14α-demethylase by various phytochemicals from brassicales, i.e., glucosinolates and their potential role as putative drug molecules.

Methods: In this study, in silico analyses were performed to predict the molecular basis of various glucosinolates as a potential inhibitor of lanosterol-14α-demethylase protein, which is a key regulator of fungal membrane biosynthesis and its pharmacodynamics and toxicity profile. 3d structures of various glucosinolates were retrieved from PubChem, and the target protein, lanosterol-14α-demethylase (Pdb ID- 4lxj), was retrieved from the RCSB protein data bank. Molecular docking and interactions were carried out using the PyRx software using the AutoDOCK toolbar with default parameters. Dru- LiTo, ORISIS web servers were used to predict various drug likeliness predictions and Lipinski's Rule of 5, whereas admetSAR was used for prediction of toxicity, and PASS Program was used to study the antifungal and antimicrobial properties of these compounds.

Results: This study shows that among the different compounds screened, gluconasturtiin, Glucotropaeolin, and Indolylmethyl-Glucosinolate showed the highest binding energies of -8.7 kcal/mol, -8.5 kcal/mol, and -8.3 kcal/mol with the lanosterol-14α-demethylase, respectively. Further all the compounds follow the Lipinski's rule as well as they are found to be non-carcinogenic and non-cytotoxic in nature. These compounds also show antifungal properties.

Conclusion: This study thus reveals that various glucosinolates interact with the ERG13 enzyme at various amino acid positions, which behaves as a catalytic site, thus indicates the probable mechanism of inactivation, and subsequently, these can be used as potential drug molecules. In vitro studies can be taken to further examine the utility of these compounds as antifungal agents.