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SARS-CoV-2’s main protease (Mpro) interaction with ligands has been explored with a myriad of crystal structures, most of the monomers. Nonetheless, Mpro is known to be active as a dimer but the relevance of the dimerization in the ligand-induced conformational changes has not been fully elucidated. We systematically simulated different Mpro-ligand complexes aiming to study their conformational changes and interactions, through molecular dynamics (MD). We focused on covalently bound ligands (N1 and N3, ∼9 μs per system both monomers and dimers) and compared these trajectories against the apostructure. Our results suggest that the monomeric simulations led to an unrealistically flexible active site. In contrast, the Mpro dimer displayed a stable oxyanion-loop conformation along the trajectory. Also, ligand interactions with residues His41, Gly143, His163, Glu166 and Gln189 are postulated to impact the ligands' inhibitory activity significantly. In dimeric simulations, especially Gly143 and His163 have increased interaction frequencies. In conclusion, long-timescale MD is a more suitable tool for exploring in silico the activity of bioactive compounds that potentially inhibit the dimeric form of SARS-CoV-2 Mpro. Communicated by Ramaswamy H. Sarma

Gold nanoparticles (NPs) combined with Lewis bases, such as piperazine, were found to perform selective hydrogenation reactions via the heterolytic cleavage of H2. Since gold nanoparticles can be prepared by many different methodologies and using different capping ligands, in this study, we investigated the influence of capping ligands adsorbed on gold surfaces on the formation of the gold–ligand interface. Citrate (Citr), poly(vinyl alcohol) (PVA), polyvinylpyrrolidone (PVP), and oleylamine (Oley)-stabilized Au NPs were not activated by piperazine for the hydrogenation of alkynes, but the catalytic activity was greatly enhanced after removing the capping ligands from the gold surface by calcination at 400 °C and the subsequent adsorption of piperazine. Therefore, the capping ligand can limit the catalytic activity if not carefully removed, demonstrating the need of a cleaner surface for a ligand–metal cooperative effect in the activation of H2 for selective semihydrogenation of various alkynes under mild reaction conditions.

We have developed a dual enzymatic system assay involving liquid chromatography-mass spectrometry (LC–MS) to screen AChE and BACE1 ligands. A fused silica capillary (30 cm × 0.1 mm i.d. × 0.362 mm e.d.) was used as solid support. The co-immobilization procedure encompassed two steps and random immobilization. The resulting huAChE+BACE1-ICER/MS was characterized by using acetylcholine (ACh) and JMV2236 as substrates. The best conditions for the dual enzymatic system assay were evaluated and compared to the conditions of the individual enzymatic system assays. Analysis was performed in series for each enzyme. The kinetic parameters (KMapp) and inhibition assays were evaluated. To validate the system, galantamine and a β-secretase inhibitor were employed as standard inhibitors, which confirmed that the developed screening assay was able to identify reference ligands and to provide quantitative parameters. The combination of these two enzymes in a single on-line system allowed possible multi-target inhibitors to be screened and identified. The innovative huAChE+BACE1-ICER/MS dual enzymatic system reported herein proved to be a reliable tool to identify and to characterize hit ligands for AChE and BACE1 in an enzymatic competitive environment. This innovative system assay involved lower costs; measured the product from enzymatic hydrolysis directly by MS; enabled immediate recovery of the enzymatic activity; showed specificity, selectivity, and sensitivity; and mimicked the cellular process.

Bacterial glycoside hydrolase 1 (GH1) enzymes with 6-phospho-β-galactosidase and 6-phospho-β-glucosidase activities have the important task of releasing phosphorylated and nonphosphorylated monosaccharides into the cytoplasm. Curiously, dual 6-phospho-β-galactosidase/6-phospho-β-glucosidase (dual-phospho) enzymes have broad specificity and are able to hydrolyze galacto- and gluco-derived substrates. This study investigates the structure and substrate specificity of a GH family 1 enzyme from Bacillus licheniformis, hereafter known as BlBglC. The enzyme structure has been solved, and sequence analysis, molecular dynamics simulations, and binding free energy calculations offered evidence of dual-phospho activity. Both test ligands p-nitrophenyl-β-d-galactoside-6-phosphate (PNP6Pgal) and p-nitrophenyl-β-d-glucoside-6-phosphate (PNP6Pglc) demonstrated strong binding to BlBglC although the pose and interactions of the PNP6Pglc triplicates were slightly more consistent. Interestingly, known specificity-inducing residues, Gln23 and Trp433, bind strongly to the ligand O3 hydroxyl group in the PNP6Pgal-BlBglC complex and to the ligand O4 hydroxyl group in the PNP6Pglc-BlBglC complex. Additionally, the BlBglC-His124 residue is a major contributor of hydrogen bonds to the PNP6Pgal O3 hydroxyl group but does not form any hydrogen bonds with PNP6Pglc. On the other hand, BlBglC residues Tyr173, Tyr301, Gln302, and Thr321 form hydrogen bonds with PNP6Pglc but not PNP6Pgal. These findings provide important details of the broad specificity of dual-phospho activity GH1 enzymes.

A quantum-chemical study based on the Kohn–Sham density functional theory (DFT) has been performed in order to investigate the asymmetric Heck–Matsuda (HM) reactions involving a chiral N,N ligand pyrimidine-oxazoline. The oxidative addition (OA) of arenediazonium cation was analyzed to provide further insights in the unexpected high reactivity of N,N-ligated palladium(0)-based catalysts observed in these HM processes. DFT calculations suggest that the ionogenic nature of metal center promoted by the arenediazonium cation addition increases the electronic reactivity of palladium(0) toward the donor N,N ligand. The concerted and multi-step mechanisms were computed for the OA step, in which the cationic aryl-palladium(II) complex formation was revealed as the thermodynamic driving force for this process. The importance of conformational analyses was highlighted, particularly when an acyclic alkenol olefin is taken as substrate, since its absence could lead to misleading predictions about the selectivity of these HM systems. While the enantioselectivity is controlled by the combination of steric and dispersion interactions between ligand and substrate, the regioselectivity is mostly oriented by the electronic nature of olefinic carbons. DFT predictions on the selectivity were shown to be in quantitative agreement with experimental results.

Fundação de Apoio a Pesquisa e à Inovação Tecnológica do Estado de Sergipe - FAPITEC/SE Density Functional Theory (DFT) calculations and its time dependent approach (TDDFT) have been performed to investigate the ligand effect on the structural and optical properties of the Au13 and Au13 3+ clusters. In the first part of this work, it has been investigated through the analysis of the potential energy curves, the most favorable coordination site of the NH3, PH3, SCH3 and SeCH3 ligands on the Au13 cluster. The results show that the NH3 and PH3 ligands bind preferentially on top site, while for the other ligands the coordination to the (111) site is energetically more favorable. In addition, it was studied the ligand influence on the structural, electronic and optical properties of the Au13L, where L = NH3, N(CH3)3, PH3, P(CH3)3, SCH3, SCH2Ph, SCH(CH3)NH2, SCH(CH3)Cl, SPh, SPhCH3 , SPhCOOH and SeCH3. The analysis of the electronic stabilities reveals that the Au13SCH(CH3)Cl and Au13NH3 are the most stable among the other clusters of the thiolate or selenolate and of the phosphine or amine-ligated groups, respectively. The ligand effect on the optical absorption spectra of Au13L is relatively small, in which the main change is observed in the intensity of the highest energy peak. In the second part of this work, it has been developed a systematic structural analysis of Au13L8 3+, where L = SCH3, SeCH3, SCH2OCH3 e S(CH3)2NH2, to exam the influence of different ligands. Binding energy calculations indicate that the gold core is more stabilized by the ligand in the following sequence S(CH3)2NH2 > SCH2OCH3 > SeCH3 > SCH3. Natural Bond Analysis (NBO) shows that the strongest electron donation occurs from a lone pair orbital on the sulfur and selenium atoms to the antibonding acceptor o* (Au−S) and o* (Au−Se), respectively. TDDFT calculations have been performed to simulate the optical absorption spectra of Au13L8 3+ in gas phase and under the effect of solvents with different polarities. The absorption spectrum of [Au13(S(CH2)2NH2)8]3+ shows a spectral profile that differs considerably from the others in gas phase and which is strongly affected by solvent. Cálculos da teoria do funcional de densidade (do inglês, Density Functional Theory – DFT) e sua abordagem dependente do tempo (TDDFT) foram realizados para investigar a influência de diferentes ligantes nas propriedades estruturais e ópticas dos clusters de ouro Au13 e Au13 3+. Inicialmente foi investigado, por meio das curvas de energia potencial, o sítio de coordenação mais favorável de diferentes ligantes (NH3, PH3, SCH3 e SeCH3) no cluster de Au13. Os resultados mostram que o ligante aminado e o fosfinado se coordenam preferencialmente ao sítio on top, enquanto que, para os demais ligantes, a coordenação ao sítio da face (111) se mostra energeticamente mais favorável. Em seguida, foi estudada a influência dos ligantes sobre as propriedades estruturais, eletrônicas e ópticas do cluster de Au13L, sendo L = NH3, N(CH3)3, PH3, P(CH3)3, SCH3, SCH2Ph, SCH(CH3)NH2, SCH(CH3)Cl, SPh, SPhCH3, SPhCOOH e SeCH3. A análise dos resultados da estabilidade eletrônica revelou que os clusters de Au13SCH(CH3)Cl e Au13NH3 são os mais estáveis dentre àqueles que pertencem ao grupo dos tiolados ou selenolado e ao grupo dos aminados e fosfinados, respectivamente. Posteriormente, foi avaliada a influência dos ligantes sobre os espectros de absorção do Au13L, onde o principal efeito está na intensidade da banda de mais alta energia. Na segunda parte deste trabalho foi realizada uma análise estrutural do Au13L8 3+, onde L = SCH3, SeCH3, SCH2OCH3 e S(CH3)2NH2. Cálculos de energia de ligação indicam que o Au13 é mais estabilizado pelo ligante de acordo com a sequência: S(CH3)2NH2 > SCH2OCH3 > SeCH3 > SCH3. A análise dos orbitais naturais de ligação (do inglês, Natural Bond Orbitals ‒NBO) mostra que a doação eletrônica mais forte ocorre dos orbitais não ligantes sobre os átomos de enxofre ou selênio para os orbitais antiligantes o* (Au-S) e o* (Au-Se), respectivamente. Além disso, ela permitiu entender a origem da maior estabilidade do [Au13(S(CH2)2NH2)8]3+. Os espectros ópticos de absorção do Au13L8 3+ foram calculados em fase gasosa e sob o efeito de solventes. O espectro de absorção do [Au13(S(CH2)2NH2)8]3+ mostra um perfil espectral que difere dos demais clusters em fase gasosa e o mesmo é fortemente afetado pelo efeito do solvente. São Cristóvão, SE

Amphiphilic ruthenium bipyridine complexes based on 1,3,4-oxadiazole-pyridine ligands (L1, L2) were synthesized and characterized by 1H NMR, UV–Vis spectroscopy, electrochemistry and UV–Vis spectroelectrochemistry. The free ligands and the respective ruthenium(II) complexes exhibit an intraligand π−π∗ absorption band in the UV region that overlaps with the MLCT bands. The [Ru(bpy)2(L2)](PF6)2 complex with a bidentated L2 ligand did not form a stable monolayer in water-air interface demonstrating the relevance of coordination geometry on the molecular packing properties. In contrast, stable Langmuir-Blodgett films of the [Ru(bpy)2(L1)Cl]PF6 complex (RuL1) exhibiting reversible and fast spectroelectrochemical properties associated with the Ru(III/II) redox couple were obtained, where redox site inactivation become relevant above 20 monolayers where the current leveled up. Thin LB films were deposited on poly(bithiophene) to enhance its photoelectrochemical properties and realize photoresponsive AND and OR logic gate devices.

O Ferro é um micronutriente essencial para o fitoplâncton, presente em pequenas concentrações no meio marinho, apesar que, em zonas costeiras como a Plataforma Continental Sul Brasileira possa ser encontrado em concentrações mais elevadas. Sua biodisponibilidade e solubilidade na água do mar dependem principalmente da sua complexação por moléculas orgânicas. Deste modo, muitos estudos têm sido desenvolvidos e relacionados à especiação orgânica deste elemento. Para tanto, tem se buscado o aprimoramento e a implementação de métodos mais eficientes para a especiação orgânica desse elemento. Conhecendo a escassez de trabalhos relacionados à especiação orgânica de ferro na costa brasileira, principalmente na região sul, onde existe altas concentrações deste elemento. Este estudo tem como objetivo avaliar a especiação orgânica do ferro dissolvido na Plataforma Continental do Sul do Brasil (PCSB). Para isso, esse estudo foi divido em dois capítulos: o primeiro, descreve a adaptação do método voltamétrico para a especiação orgânica de ferro (CLE-AdCSV) usando salicilaldoxima (SA) e a segunda parte deste trabalho foi feita a aplicação do método nas amostras oriundas da PCSB. No primeiro capítulo foram adaptados dois métodos: um para determinação do ferro e outro para especiação orgânica, além disso foram feitos estudos de estabilidade e intensidade do sinal analítico. Para garantir a repetibilidade, foi implementado um purga de ar filtrado acoplado a um sistema de vácuo na célula voltamétrica, a temperatura, o pH e o condicionamento da mesma também foram otimizados.Foram avaliados o potencial de deposição e a concentração de SA, tendo sido observado a melhor concentração 25μM de SA e 0 V como o melhor potencial de deposição. Dessa forma, para a análise de especiação orgânica de ferro algumas adaptações do método (CLE-AdCSV) foram feitas, dentre elas, a velocidade de varredura e o tempo de equilíbrio entre os ligantes naturais e a SA. Desse modo, adquiriu-se dois métodos nesse capítulo, sendo ambos validados usando um material certificado, obtendo-se limites de quantificação (LQ) para a determinação de Fe total e especiação de 1,06 nM e 1,43 nM, respectivamente. A partir da confiabilidade de ambos métodos foi possível investigar a biogeoquímica do ferro, em relação a especiações orgânica, na região escolhida como local de coleta de amostras. Assim, no segundo capítulo é descrito as regiões amostrais, uma localizada em frente ao Farol do Albardão e outra na região do Cabo Santa Marta, entre 32°S e 28,5°S, respectivamente. A bordo do Navio Oceanográfico Atlântico Sul foram coletadas amostras de água durante o verão e inverno de 2015 no transecto do Albardão e durante o inverno de 2015 em Santa Marta. Em ambas as localidades, as amostras de água foram com garrafas Go-Flo (coletadas superfície e fundo) no verão e um sistema do tipo “fish” (somente superfície) no inverno. Foram analisados nutrientes inorgânicos dissolvidos (nitrato, silicato e fosfato) e perfis verticais de temperatura e salinidade, obtidos utilizando um CTD. As maiores concentrações de ferro dissolvido (FeD) foram verificadas na pluma do Rio da Prata em ambos transectos. As concentrações de FeD e todos os nutrientes analisados foram menores nas massas de água mais oligotróficas, tais como, Água Tropical (AT) e Água Subtropical de Plataforma, com exceção do nitrato em Santa Marta. Essa anomalia também foi observada na presença de ligantes orgânicos na mesma região, associada à produção biológica. Como esperado, foram encontradas baixas concentrações de ferro livre, Fe+3, não chegando a 1% do FeD na amostra. Além disso, foram verificadas altas capacidades de complexação (L), e excesso de ligantes (eL) em todos os transectos, superando os valores de ferro dissolvido encontrados. Os valores da constante de estabilidade apresentado em todos os períodos amostrados variaram entre 12,32 – 8,97 o que indica até três classes de ligantes. Os resultados destes transectos foram comparados com outras localidades do mundo, mostrando semelhança com regiões ricas em ácidos húmicos, regiões de descarga fluviais e altas produções biológicas. As altas concentrações de FeD sobre a plataforma podem influenciar a formação de ligantes, gerando alta capacidade de complexação ao longo de todos os transectos, mantendo o ferro solúvel na coluna d’água e, consequentemente, tornando-o biodisponível. Assim acredita-se que a ação de correntes oceânicas pode atuar na distribuição deste elemento, em sua forma solúvel, para o oceano adjacente o que promoveria a fertilização de locais mais afastados da costa. Iron is an micronutrient for phytoplankton, its concentration is small in the marine environment, although, in coastal areas like the Southern Brazilian Continental Shelf it can be found in higher concentrations. Its bioavailability and solubility in seawater depends on mainly your complexation by organic molecules. In this way, many studies have been developed and related to organic speciation of this element. To this end, has sought the improvement and the implementation of more efficient methods for organic speciation of this element. Knowing the shortage of organic speciation-related jobs in the Brazilian coast, mainly in the South, where there are high concentrations of the element. This study aims to evaluate the organic speciation of dissolved iron in the Continental Shelf of southern Brazil (PCSB). To this end, this study was divided into two chapters: the first describes the adaptation of two voltammetrics methods CLE-AdCSV using salicylaldoxime (SA) and the second presents organic speciation of iron in PCSB. In the first chapter were adapted two methods: one for determination of iron and another for organic speciation. In this chapter, the results guaranteed two factors signal stability and signal strength. For repeatability: was implemented one plus purge system of filtered air and a vacuum system in cell, temperature, pH and conditioning of this were also adaptations necessary for the stability of the signal. For a better intensity were tests of potential deposition and concentration of SA, having been observed better concentrating 25µM de SA and 0 V as the best potential for deposition. That way in the analysis of organic speciation adaptations were also needed, including the scanning speed and time of balance between the natural ligands and the SA. Thereby acquired two methods in this chapter, both being validated using a material certificate, obtaining low limits of quantification (LQ) .1.06 nM for the determination of Fe and 1.43 nM for speciation. The best method was used for determining LQ. From the reliability of both methods it was possible to investigate the Biogeochemistry of iron in relation to organic speciation in the region chosen as site of specimen collection. Thus, in chapter two described that there were two sampling campaigns in two regions, one located in front of the Albardão and another lighthouse in the Cape Santa Marta, between 32° S and 28.5° S. On board the ship South Atlantic Oceanographic water samples were collected during the summer and winter of 2015 in transect of the Albardão and during the winter of 2015 in Santa Marta. In both localities, water samples were sampled with Go-Flo bottles (collected surface and bottom) in the summer and a system of type "fish" (surface) in the winter. Under such samples were analyzed the dissolved inorganic nutrients (nitrate, phosphate and silicate) and vertical profiles of temperature and salinity, obtained using a CTD. The largest concentrations of dissolved iron (dFe) were observed in the plume of the Río de la Plata in both transects. The dFe and all the nutrients analyzed were lower in more oligotrophic water masses, Tropical Water (WT) and Subtropical Shelf Water (SSW), except for nitrate in Santa Marta. This anomaly was also observed in the presence of organic ligands in the same region, associated with organic production. The largest concentrations of dissolved iron (EDF) were observed in the plume of the La Plat River in both transects. As expected, were found low concentrations of free iron, Fe+ 3, not reaching 1% of the dFe. In addition, verified high complexation capacities (L), and excess ligand (eL) on all transects, exceeding the values of dissolved iron found. The stability constant values, presented in all periods sampled ranged from 12.32-8.97 indicating up to three classes of ligands. The results of these transects were compared with other places in the world showing similarity to regions rich in humic acids, river discharge and high regions organic production. The high concentrations of dFe on the shelf can influence the formation of ligand, generating high complexation capacity along all transects, keeping the iron soluble in the water column and, consequently the making it bioavailable. Thus, it is believed that the action of ocean currents can act in the distribution of this element in your form soluble, adjacent to the ocean which would promote fertilization of these sites further away from the coast.

Cation−π interactions in a set of ruthenophanes [Ru(η6-CnHn)(NH3)3]2+ (n = 16, 18, 20, 22, and 24) (1–9), containing multibridged cyclophanes as ligands, including [2.2]paracyclophane and its multibridged analogs, [2n]cyclophanes, are analyzed in terms of SAPT0/TZP and Su–Li EDA analyses. The calculations reveal that the coordination with cation [Ru(NH3)3]2+ affects the structures of [2n]ciclophane ligands, mainly the planarity of the coordinating ring. The EDA results show that the gradual addition of ethano bridges in [2n]cyclophanes tends to strengthen the cation−π interaction between [Ru(NH3)3]2+ and [2n]cyclophane. Both Su–Li EDA and SAPT0 are in line, suggesting that the cation−π interactions present a predominant covalent character in complexes 1–9.

Phosphine ruthenate complexes containing the non-innocent ligands 4-chloro-1,2-phenylenediamine (opda-Cl) and 3,3′,4,4′-tetraamminebiphenyl (diopda) were synthesized and characterized by means of X-ray diffraction, electrochemistry, 31P{1H} NMR and electronic spectroscopies. Crystals of cis-[RuCl2(dppb)(bqdi-Cl)] complex were isolated as a mixture of two conformational isomers due to different positions of the chlorine atoms of the o-phenylene ligand in relation to the P1 atom of the phosphine moiety.

Most physiological effects of thyroid hormones are mediated by the two thyroid hormone receptor subtypes, TRalpha and TRbeta. Several pharmacological effects mediated by TRbeta might be beneficial in important medical conditions such as obesity, hypercholesterolemia and diabetes, and selective TRbeta activation may elicit these effects while maintaining an acceptable safety profile. To understand the molecular determinants of affinity and subtype selectivity of TR ligands, we have successfully employed a ligand- and structure-guided pharmacophore-based approach to obtain the molecular alignment of a large series of thyromimetics. Statistically reliable three-dimensional quantitative structure-activity relationship (3D-QSAR) and three-dimensional quantitative structure-selectivity relationship (3D-QSSR) models were obtained using the comparative molecular field analysis (CoMFA) method, and the visual analyses of the contour maps drew attention to a number of possible opportunities for the development of analogs with improved affinity and selectivity. Furthermore, the 3D-QSSR analysis allowed the identification of a novel and previously unmentioned halogen bond, bringing new insights to the mechanism of activity and selectivity of thyromimetics.

5-HT1A receptor antagonists have been employed to treat depression, but the lack of structural information on this receptor hampers the design of specific and selective ligands. In this study, we have performed CoMFA studies on a training set of arylpiperazines (high affinity 5-HT1A receptor ligands) and to produce an effective alignment of the data set, a pharmacophore model was produced using Galahad. A statistically significant model was obtained, indicating a good internal consistency and predictive ability for untested compounds. The information gathered from our receptor-independent pharmacophore hypothesis is in good agreement with results from independent studies using different approaches. Therefore, this work provides important insights on the chemical and structural basis involved in the molecular recognition of these compounds.