In silico approach to select new natural-based compounds targeting tyrosinase

Melanogenesis is enzymatically regulated by tyrosinase (TYR, EC 1.14.18.1), which catalyzes the two limiting reactions of the entire biosynthesis process. It is well-known that TYR can be efficiently inhibited by natural and synthetic phenols [1,2], suggesting a therapeutic strategy for the treatment of human hyperpigmentation-related diseases [3]. We began our investigation by considering that the 3-methoxy-4-hydroxyphenyl fragment might display improved metabolic stability and establish more favorable interaction with the bicopper active site when compared to phenolic chemotypes as physiological substrate tyrosine. To perform this study, we collected a large number of natural compounds, that share a certain degree of similarity with the natural products (NPs) as vanillin and sinapyl alcohol (Figure 1) possessing the selected key chemical motif. By employing this pair of 3-methoxy-4-hydroxyphenyl-based derivatives as queries we retrieved the first collection of compounds from the Database "COCONUT" (COlleCtion of Open Natural prodUcTs, https://coconut.naturalproducts.net), which is one of the most recent and comprehensive library of NPs [4]. To enrich our library of 3-methoxy-4-hydroxyphenyl-inspired molecules we also employed the Specs database (https://www.specs.net) of commercially available compounds. All collected compounds were in silico screened using the pharmacophore model based on previously reported active inhibitors [2]. This combined procedure provided a focused library of compounds from natural source that will be preliminary tested in in vitro assay against Agaricus bisporus tyrosinase. As a result, we will be able to obtain information for next series of inhibitors