Unravelling the mechanism of tyrosinase inhibition by arylpiperidine and arylpiperazine derivatives: A computational approach

Abstract

Melanogenesis produces human melanin, which protects against UV radiation but can lead to skin issues and severe cancers if not appropriately regulated. The enzyme tyrosinase (TYR) plays a crucial role in melanin production, so inhibiting it is an essential target for controlling melanin levels. This study applied classical and quantum computational methods to examine how TYR interacts with inhibitors based on arylpiperidine and arylpiperazine. Using classical molecular dynamics (MD) simulations and the Linear Interaction Energy (LIE) method, we identified a strong correlation (r² = 0.963) between computational and experimental binding free energies, underscoring the accuracy of these approaches. Additionally, residual decomposition analysis revealed the critical role of electrostatic interactions with Cu²⁺ ions at the active site, along with van der Waals interactions involving key residues, including Phe197, Pro201, Val218, Asn205, and Arg209, which are pivotal for inhibitor effectiveness. These findings are further supported by Free Energy Perturbation (FEP) calculations, which demonstrate excellent agreement with experimental data (r² = 0.843), providing robust validation of the computational models. Additionally, quantum mechanical (QM) calculations using the DFT (wB97XD/6-311++G(d,p)) method uncovered electronic factors that influence inhibitor binding. Analyzing the frontier molecular orbitals (FMOs) and QM descriptors for L04, L08 and L19 inhibitors provided insights into TYR binding by arylpiperidine and arylpiperazine-based compounds. This thorough computational analysis improves our understanding of TYR inhibition and helps guide the development of treatments for conditions related to melanogenesis.