Structure-Based Virtual Screening of Furan-1,3,4-Oxadiazole Tethered N-phenylacetamide Derivatives as Novel Class of hTYR and hTYRP1 Inhibitors

Abstract

Human tyrosinase (hTYR) is a key and rate-limiting enzyme along with human tyrosinase-related protein-1 (hTYRP1), which are among the most prominent targets of inhibiting hyper pigmentation and melanoma skin cancer. In the current in-silico computer-aided drug design (CADD) study, the structure-based screening of sixteen furan-1,3,4-oxadiazole tethered <i>N</i>-phenylacetamide structural motifs <b>BF1</b>-<b>BF16</b> was carried out to assess their potential as hTYR and hTYRP1 inhibitors. The results revealed that the structural motifs <b>BF1</b>-<b>BF16</b> showed higher binding affinities towards hTYR and hTYRP1 than the standard inhibitor kojic acid. The most bioactive lead furan-1,3,4-oxadiazoles <b>BF4</b> and <b>BF5</b> displayed stronger binding in affinities (-11.50 kcal/mol and -13.30 kcal/mol) than the standard drug kojic acid against hTYRP1 and hTYR enzymes, respectively. These were further confirmed by MM-GBSA and MM-PBSA binding energy computations. The stability studies involving the molecular dynamics simulations also provided stability insights into the binding of these compounds with the target enzymes, wherein it was found that they remain stable in the active sites during the 100 ns virtual simulation time. Moreover, the ADMET, as well as the medicinal properties of these novel furan-1,3,4-oxadiazole tethered <i>N</i>-phenylacetamide structural hybrids, also showed a good prospect. The excellent in-silico profiling of furan-1,3,4--oxadiazole structural motifs <b>BF4</b> and <b>BF5</b> provide a hypothetical gateway to use these compounds as potential hTYRP1 and hTYR inhibitors against melanogenesis.