In silico investigation on the inhibitory potential of natural polyphenolics against Lanosterol 14α-Demethylase to discover novel antifungal lead compounds

Abstract

Lanosterol 14α-Demethylase is considered one of the main targets for the development of novel therapeutics against fungal diseases. In this research, more than 100 natural polyphenolic compounds from honeybee propolis were introduced to blind and targeted molecular docking protocols to investigate their antifungal potential against the fungal enzyme. Finally, the compounds with the lowest binding energies were subjected to 250 ns molecular dynamics (MD) simulations. Accordingly, it turns out that three compounds, Dehydroabietic acid (DAA), 3-Hydroxy-2,2-dimethyl-8-prenylchromane-6-propenoic acid (3HPP), and (2R,3R)-6[1-(4′-Hydroxy-3′-methoxyphenyl) (HYM), bound to the catalytic pocket with the lowest binding energies of −10.4, −10.0, −9.8 kcal/mol, respectively. According to MD simulations results, binding of these three compounds to the receptor changed the RMSF magnitudes of residues in the catalytic pocket. Also, DAA and 3HPP significantly changed the structural dynamics of the protein, especially in regions vital for substrate binding and enzymatic activity, suggesting potential disruption of the enzyme's function and hindrance to fungal growth. These compounds caused notable decreases in Rg and SASA of the protein, indicating increased structural compactness. Furthermore, DAA and 3HPP significantly impacted the protein's mobility patterns, potentially impeding its function. Binding free energy calculations also revealed DAA's superior affinity, making it the top candidate among the studied ligands. According to their predicted pharmacokinetics and toxicity properties, DAA and 3HPP, with good pharmacokinetic properties and low toxicities, caused the highest instability in the protein structure, so they can be nominated as the most effective antifungal agents against Lanosterol 14α-Demethylase to further investigations to prove their efficiencies.