Anilino-1,4-naphthoquinones as potent mushroom tyrosinase inhibitors: in vitro and in silico studies.

Tyrosinase, a pivotal enzyme in melanin synthesis, is a primary target for the development of depigmenting agents. In this work, in vitro and in silico techniques were employed to identify novel tyrosinase inhibitors from a set of 12 anilino-1,4-naphthoquinone derivatives. Results from the mushroom tyrosinase activity assay indicated that, among the 12 derivatives, three compounds (1, 5, and 10) demonstrated the most significant inhibitory activity against mushroom tyrosinase, surpassing the effectiveness of the kojic acid. Molecular docking revealed that all studied derivatives interacted with copper ions and amino acid residues at the enzyme active site. Molecular dynamics simulations provided insights into the stability of enzyme-inhibitor complexes, in which compounds 1, 5, and particularly 10 displayed greater stability, atomic contacts, and structural compactness than kojic acid. Drug likeness prediction further strengthens the potential of anilino-1,4-naphthoquinones as promising candidates for the development of novel tyrosinase inhibitors for the treatment of hyperpigmentation disorders.

Structural dynamics and susceptibility of isobutylamido thiazolyl resorcinol (ThiamidolTM) against human and mushroom tyrosinases.

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 (ThiamidolTM) 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 ThiamidolTM 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 ThiamidolTM 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 ThiamidolTM/mTyr complex than the ThiamidolTM/hTyr system, supported by the lower binding affinity of ThiamidolTM/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 ThiamidolTM scaffold.Communicated by Ramaswamy H. Sarma.

The investigation of binary and ternary sulfobutylether-ß-cyclodextrin inclusion complexes with asiaticoside in solution and in solid state.

Asiaticoside (AS) is poorly water-soluble compound that can lead to low the bioavailability. The aims of this study were to determine the cyclodextrin (CD) solubilization of AS and characterize binary AS/CD and ternary AS/CD/polymer complexes in solution- and solid-state. Thermal stability of AS through heating process was determined and found that It could withstand by heating through sonication method. Phase-solubility profiles showed that ß-cyclodextrin (ßCD) exhibited the greatest solubilizing effect but sulfobutylether-ßCD (SBEßCD) was selected for further investigations due to its relatively high complexation efficiency (CE) value. The effect of polymers that were poloxamer 407 (P407) and chitosan (CS) on CD solubilization were investigated. It was found that the increment of CE was resulted from the formation of ternary complexes or complex aggregates with confirmed by dynamic light scattering and transmission electron microscopy. Proton nuclear magnetic resonance (1H NMR) data indicated that the cyclohexane moiety of AS was totally inserted into the hydrophobic inner cavity of SBEßCD in the presence or absence of polymer. The molecular modeling study displayed the binding orientation of such complex which correlated to 1H NMR result. The solid state characterized by Fourier transform infra-red, differential scanning calorimetry and powder X-ray diffraction demonstrated the formation of binary AS/SBEßCD and ternary AS/SBEßCD/polymer inclusion complexes. The enhancement of AS dissolution was achieved in both binary and ternary complexes. The permeation study showed that ternary AS/SBEßCD/CS nanoparticles exhibited a promising controlled drug release nanocarrier.

Structural insight into the recognition of S-adenosyl-L-homocysteine and sinefungin in SARS-CoV-2 Nsp16/Nsp10 RNA cap 2'-O-Methyltransferase.

The recent ongoing coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to rapidly spread across the world. To date, neither a specific antiviral drug nor a clinically effective vaccine is available. Among the 15 viral non-structural proteins (nsps), nsp16 methyltransferase has been considered as a potential target due to its crucial role in RNA cap 2'-O-methylation process, preventing the virus detection by cell innate immunity mechanisms. In the present study, molecular recognition between the two natural nucleoside analogs (S-adenosyl-l-homocysteine (SAH) and sinefungin (SFG)) and the SARS-CoV-2 nsp16/nsp10/m7GpppAC5 was studied using all-atom molecular dynamics simulations and free energy calculations based on MM/GBSA and WaterSwap approaches. The binding affinity and the number of hot-spot residues, atomic contacts, and H-bond formations of SFG/nsp16 complex were distinctly higher than those of SAH/nsp16 system, consistent with the lower water accessibility at the enzyme active site. Notably, only SFG could electrostatically interact with the 2'-OH and N3 of RNA's adenosine moiety, mimicking the methyl transfer reaction of S-adenosyl-l-methionine substrate. The atomistic binding mechanism obtained from this work paves the way for further optimizations and designs of more specific SARS-CoV-2 nsp16 inhibitors in the fight against COVID-19.