In Silico Investigation and Evaluation of New Potent Tyrosinase Related Protein-۱ Inhibitors Using Molecular Dynamics Simulations and Docking Study

Tyrosinase is one of the important enzymes and corresponds to skin diseases such as hyperpigmentation and melanogenesis. In medicinal chemistry studies, the tyrosinase-related protein ۱ is one of the main target proteins related to these diseases. In recent years, some molecules have been studied and investigated as agonist inhibitors for TRP۱. Kojic acid, ellagic acid, L-ascorbic acid, tranexamic acid and hydroquinone are some small molecules that have been investigated as lead compounds and finally approved drugs. But because of some side effects that have been reported, research for achieving better drugs continues. The in-silico study approach is one of the basic steps in drug design and drug optimization processes. In our work, in-silico study and evaluation were applied through virtual screening tools such as molecular docking and molecular dynamics simulations to investigate new potent inhibitors of this target protein. The crystallographic data of the complex between kojic acid as a standard inhibitor and the target protein were investigated using specific software platforms. Then, some similar molecules were selected using an algorithm applied in the zinc۱۵ databank. The molecular docking simulation was performed to achieve the best binding affinity and docking scores. A comparison among standard inhibitors and high-scoring selected ligands was performed. Three ligands had the best results. The molecular dynamics simulation was applied to the detailed study of the interaction between top-selected ligands and TYRP۱ as the target protein molecule. The RMSD of alpha carbon atoms in the target protein, as well as the RMSF of all amino acid residues and selected ligands, were studied. The results showed that ۳-hydroxy-۶-(hydroxymethyl)-۲-methyl-۴H-pyran-۴-one (L۱) and ۲-chloro-۳-hydroxy-۶-(hydroxymethyl)-۴H-pyran-۴-one (L۲) have more potential and effectiveness than kojic acid and can be used as new potent inhibitors for TYRP۱.

کلیدواژه ها:

new inhibitors ، Tyrosinase related protein۱ ، Molecular docking ، Molecular Dynamics Simulation ، In Silico study