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Tyrosinase, a key enzyme catalyzing a rate-limiting step of the melanin production, has been the most promising target for suppressing hyperpigmentation. Although a number of tyrosinase inhibitors have been developed, most of those lack clinical efficacy as they were identified from using mushroom tyrosinase (mTyr) as the target. Previous study revealed that the inhibitory effect of isobutylamido thiazolyl resorcinol (Thiamidol TM ) on human tyrosinase (hTyr) is ∼100 times higher than that on mTyr. In the present study, we aimed to investigate the structural dynamics and susceptibility of Thiamidol TM  against hTyr and mTyr at the atomic level using molecular docking, molecular dynamics simulation, and free energy calculation based on the molecular mechanics/Poisson-Boltzmann surface area method. The obtained results revealed that the resorcinol moiety of Thiamidol TM  was found to be embedded in the catalytic copper center, interacting with H180, H202, H211, F386, and H390 residues of hTyr as well as with F264 residue of mTyr, mostly through van der Waals interactions. However, the number of destabilizing residues was found to be more pronounced in the Thiamidol TM /mTyr complex than the Thiamidol TM /hTyr system, supported by the lower binding affinity of Thiamidol TM /mTyr complex as well as the higher water accessibility and the lower number of atomic contacts at the active site of mTyr. Altogether, the structural and energetic information from this work would be useful for further optimization of more potent human tyrosinase inhibitors based on Thiamidol TM  scaffold. Communicated by Ramaswamy H. Sarma

Structural dynamics and susceptibility of isobutylamido thiazolyl resorcinol (Thiamidol TM ) against human and mushroom tyrosinases