Benzophenone derivatives (BZP), an important class of organic UV filters, are widely used in sunscreen products due to their ability to absorb in the UVA and UVB ranges. The structural, electronic, and spectral properties of BZP derivatives have been studied by density functional theory (DFT) and time-dependent DFT (TD-DFT) methods. DFT/B3LYP with the 6-31G(d) basis set is an accurate method for optimizing the geometry of BZPs. The absorption maxima obtained from the TD-DFT calculations in a vacuum were in agreement with the experimental absorption bands and showed that the main electronic transitions in the UVA/UVB range present π → π* character, the major transition being HOMO → LUMO. The oscillator strength seems to increase in the presence of disubstitution at the para position. For protic substituents, the position appears to be related to the absorption band. Absorption in the UVB range occurs in the presence of para substitution, whereas ortho substitution leads to absorption in the UVA spectral region. The obtained results provide some features for BZP derivatives that can be useful for customizing absorption properties (wavelengths and intensities) and designing new BZP derivatives as sunscreens.

A elucidação das rotas de reativação da acetilcolinesterase humana (HuAChE) inibida por organofosforados é de crucial importância para o desenvolvimento de antídotos eficientes contra a intoxicação causada por agentes de guerra química. Com o objetivo de contribuir para uma melhor compreensão do mecanismo de reativação, foram aplicadas neste trabalho simulações de dinâmica molecular (DM) clássica para estudar as interações entre a pralidoxima e aminoácidos do sítio ativo da HuAChE inibida pelo agente neurotóxico tabun. Além disso, métodos híbridos de mecânica quântica/mecânica molecular (QM/MM) foram usados para propor um mecanismo de reativação para a enzima inibida. Os resultados mostraram que a DM clássica manteve a pralidoxima no interior do sítio ativo da enzima, em uma região favorável à ocorrência de uma possível reação de desfosforilação, que foi confirmada por métodos de QM/MM, levando à proposta de um mecanismo de reativação, energeticamente favorável. The elucidation of the reactivation routes of human acetylcholinesterase (HuAChE) inhibited by organophosphorous compounds is of crucial importance to the development of efficient antidotes against poisoning by chemical warfare agents. In order to contribute to a better understanding of the reactivation mechanism, we applied, in this work, classical molecular dynamics (MD) simulations to study the interactions between pralidoxime and the active site's amino acids of HuAChE inhibited by the neurotoxic agent tabun. Further, quantum mechanical/molecular mechanical (QM/MM) hybrid methods were used to propose a reactivation mechanism for the inhibited enzyme. The results showed that the classic MD kept pralidoxime inside the enzyme's active site, in a favorable region to the occurrence of possible reactions of dephosphorilation, which were confirmed by QM/MM methods, and lead to the proposition of an energetically favorable mechanism of reactivation.

One of the most interesting aspects of Trypanosoma cruzi is its adaptation to obtain sialic acid from its host, fulfilling this need exclusively through the reaction catalyzed by enzymatically active trans-sialidase (aTS), thought to play an important role in the pathogenesis of Chagas' disease. Herein, we report that 2-difluoromethyl-4-nitrophenyl-3,5-dideoxy-d-glycero-alpha-d-galacto-2-nonulopyranosid acid (NeuNAcFNP) inactivates aTS time- and dose-dependently, and this inhibition was not relieved removing the inhibitor. Also, NeuNAcFNP causes a decrease in infection of mammalian cells. Characterization of labeled aTS by matrix-assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry revealed that inactivation of the enzyme occurs through formation of a covalent bond between Arg245 and Asp247 and the inhibitor aglycone. Participation of Asp247 in the catalytic mechanism was proved by constructing a TSD247A mutant, which presents only residual activity. Molecular dynamic simulations indicate that the D247A mutation results in a more open catalytic cleft. In summary, NeuNAcFNP is the first reported mechanism-based inhibitor of aTS, representing a new template for drug design and opening new possibilities for chemotherapy of Chagas' disease, as well as for the elucidation of aTS function in T. cruzi pathogenesis and biology.

Reativadores eficientes de Aceticolinesterase são fundamentais para o desenvolvimento de antídotos contra o envenenamento por pesticidas neurotóxicos e agentes de guerra química. Todavia, o mecanismo da reação de reativação e as características estruturais dos reativadores conhecidos são pouco compreendidos. Com o objetivo de estudar o comportamento dinâmico e o efeito da carga líquida do antídoto na reativação desta enzima, foi conduzido um estudo por dinâmica molecular da acetilcolinesterase humana inibida por tabun em complexo com o antídoto pralidoxima e com seu análogo deazapralidoxima nas formas neutra e aniônica. Os resultados mostraram que a carga positiva da pralidoxima é importrante para sua admissão e permanência dentro do sítio ativo. Além disso, os análogos, diferente da pralidoxima, quando colocados dentro do sítio ativo, se distanciam do resíduo serina fosforilado da enzima e são repelidos pelo potencial eletrostático na entrada do canal que conduz ao sítio ativo.Efficient acetylcholinesterase reactivators are fundamental for the development of antidotes against poisoning by neurotoxic pesticides and chemical warfare agents. However, the mechanism of the reactivation reaction and the structural characteristics of the known reactivators are poorly understood. In order to study the dynamic behavior and the effect of the antidote net charge in the reactivation of this enzyme, we carried out a molecular dynamics study of human acetylcholinesterase inhibited by tabun in complex with the antidote pralidoxime and with its deaza analogues in the neutral and anionic forms. Results show that the positive charge of pralidoxime is important for its admission and permanence inside the active site. Also, the analogues, unlike pralidoxime, when forced inside the active site, move away from the phosphorilated serine residue of the enzyme and are repelled by the electrostatic potential at the entrance of the channel that conducts to the active site. Keywords: acetylcholinesterase, molecular dynamics, tabun, antidotes, neurotoxic agents IntroductionThe intensive use of neurotoxic organophosphorous compounds as pesticides in agriculture, as well as their potential use as mass destruction agents in chemical warfare, has attracted attention to the development of efficient antidotes for this type of poisoning.1,2 However, the knowledge on the appropriate treatment for patients exposed to this kind of compounds is limited to few groups of physicians around the world. 1,2One particularly important family of lethal tactical warfare chemicals is the group known as the nerve agents, which are closely related in chemical structure and biological action to many commonly used organophosphorous insecticides, but which are much more lethal. 1,2The nerve agents are esters of phosphoric acid and are potent inhibitors of acetylcholinesterase, a fundamental enzyme for ending nervous impulses. These compounds inhibit all acetylcholinesterases, including the human enzyme (HuAChE), by phosphorylating a serine hydroxyl group (Ser203 in ...

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