A new insight into mushroom tyrosinase inhibitors: docking, pharmacophore-based virtual screening, and molecular modeling studies

Abstract

Tyrosinase, a widely spread enzyme in micro-organisms, animals, and plants, participates in two rate-limiting steps in melanin formation pathway which is responsible for skin protection against UV lights' harm whose functional deficiency result in serious dermatological diseases. This enzyme seems to be responsible for neuromelanin formation in human brain as well. In plants, the enzyme leads the browning pathway which is commonly observed in injured tissues that is economically very unfavorable. Among different types of tyrosinase, mushroom tyrosinase has the highest homology with the mammalian tyrosinase and the only commercial tyrosinase available. In this study, ligand-based pharmacophore drug discovery method was applied to rapidly identify mushroom tyrosinase enzyme inhibitors using virtual screening. The model pharmacophore of essential interactions was developed and refined studying already experimentally discovered potent inhibitors employing Docking analysis methodology. After pharmacophore virtual screening and binding modes prediction, 14 compounds from ZINC database were identified as potent inhibitors of mushroom tyrosinase which were classified into five groups according to their chemical structures. The inhibition behavior of the discovered compounds was further studied through Classical Molecular Dynamic Simulations and the conformational changes induced by the presence of the studied ligands were discussed and compared to those of the substrate, tyrosine. According to the obtained results, five novel leads are introduced to be further optimized or directly used as potent inhibitors of mushroom tyrosinase.

Inhibitory mechanisms of glabridin on tyrosinase

“…Tyrosinase plays a crucial role in melanin biosynthesis pathway that is responsible for melanogenesis of animals [3]. And it actually catalyzes the hydroxylation of tyrosine to L-DOPA (L-3, 4-dihydroxyphenylalanine) and the subsequent oxidation of L-DOPA to DOPA quinone [4,5] which transforms into melanin and other polyphenolic compounds after a series of spontaneous chemical reactions [6].…”

Prediction of dual agents as an activator of mutant p53 and inhibitor of Hsp90 by docking, molecular dynamic simulation and virtual screening

“…The pK a was calculated by the PROPKA 3.1 web server to determine which residue was more likely to adopt non-standard ionization states [27]. The main structural water molecules in the active site were kept [28]. Protein topology parameters were obtained by the GROMOS96 53a6 force field as well as the simple point charges (SPC) water model.…”

Non-specific binding sites help to explain mixed inhibition in mushroom tyrosinase activities

“…Although the double reciprocal analysis of the kinetic data produced convex graphs with negative curvature, indicating the dominancy of negative cooperativity, Hill analysis of the data suggested that negative cooperativity was dominant at low Although the assumption of mixed-type cooperativity shed light on the complex kinetics of MT activities, changes in the mode of inhibition and the advent of non-competitive and mixed-type modes of inhibition in various studies have led scientists to assume the existence of a regulatory site on MT [9,10,[24][25][26]. However, a literature review reveals that, despite the reports of MT crystal structures (with and without an inhibitor) [27] and some valuable molecular docking and simulation studies [28], no allosteric/regulatory site for MT has been reported. To explain non-competitive and mixed-type modes of inhibition in MT kinetics studies, it is necessary to explain how the ternary complex of substrate/MT/effector is formed during the enzymatic reactions.…”