Effect of strand register in the stability and reactivity of crystals from peptides forming amyloid fibrils.

Amyloids are cytotoxic protein aggregates that deposit in human tissues, leading to several health disorders. Their aggregates can also exhibit catalytic properties, and they have been used as candidates for the development of functional biomaterials. Despite being polymorphic, amyloids often assemble as cross-ß fibrils formed by in-register ß sheet layers. Recent studies of some amyloidogenic protein segments revealed that they crystallize as antiparallel out-of-register ß sheets. Such arrangement has been proposed to be responsible for the cytotoxicity in amyloid diseases, however, there is still no consensus on the molecular mechanism. Interestingly, two amyloidogenic peptide segments, NFGAILS and FGAILSS, arrange into out-of-register and in-register ß sheets, respectively, even though they solely differ by one aminoacid residue at both termini. In this work, we used density functional theory (DFT) to address how the strand register contributes into the packing and molecular properties of the NFGAILS and FGAILSS crystals. Our results show that the out-of-register structure is substantially more stable, at 0 K, than the in-register one due to stronger inter-strand contacts. Based on an analysis of the electrostatic potential of the crystal slabs, it is suggested that the out-of-register may potentially interact with negatively charged groups, like those found in cell membranes. Moreover, calculated reactivity descriptors indicate a similar outcome, where only the out-of-register peptide exhibits intrinsic reactive surface sites at the exposed amine and carboxylic groups. It is therefore suggested that the out-of-register arrangement may indeed be crucial for amyloid cytotoxicity. The findings presented here could help to further our understanding of amyloid aggregation, function, and toxicity.

Evaluación de la satisfacción de pacientes chilenos atendidos por telemedicina en consultas nutricionales / Evaluation of the Satisfaction of Chilean Patients Attended by Telemedicine in Nutritional Consultations

La telemedicina, a través del uso de plataformas de videoconferencias por Internet, se encuentra cada vez más extendida en Chile, debido a la pandemia de COVID-19 y las restricciones para controlar el virus. El nutricionista no es ajeno a esta situación y ha tenido que modificar las consultas para dar respuesta a esta nueva realidad. Sin embargo, no existe suficiente información respecto al nivel de satisfacción de los usuarios de la telemedicina, que emplea este profesional. El objetivo de la investigación fue describir la percepción de la satisfacción usuaria relacionada con las consultas nutricionales mediante la telemedicina, realizadas durante la pandemia. Se realizó un estudio observacional, descriptivo y transversal. Se reclutaron 62 pacientes de Santiago de Chile, quienes fueron atendidos en una consulta nutricional por videoconferencia. Se diseñó un cuestionario online constituido por seis ítems para determinar la aceptabilidad de la consulta nutricional por telemedicina. El rol del nutricionista en la consulta nutricional por videoconferencia tuvo un grado de satisfacción superior al 70 por cientoEl 62,9 por ciento de los encuestados prefiere que la consulta nutricional sea combinada. Solo el 50 por ciento señala que la plataforma de videoconferencia zoom favorece la relación nutricionista-paciente. La consulta nutricional por telemedicina permite controlar el estado nutricional del paciente sin necesidad de asistir de manera presencial, lo que mejora el acceso a la atención. Existe un nivel elevado de aceptación por parte de los pacientes que han recibido atención nutricional por telemedicina(AU)

Telemedicine, through the use of Internet videoconferencing platforms, is increasingly widespread in Chile, as a consequence of the COVID-19 pandemic and the restrictions to control the virus. The nutritionist is no stranger to this situation and has had to modify consultations to respond to this new reality. However, there is insufficient information regarding the level of satisfaction of telemedicine users employed by this professional. The objective of the research was to describe the perception of user satisfaction related to nutritional consultations through telemedicine, carried out during the pandemic. An observational, descriptive and cross-sectional study was developed. Sixty-two patients were recruited from Santiago, Chile, who were attended in a nutritional consultation by videoconference. An online questionnaire consisting of six items was designed to determine the acceptability of the nutritional consultation by telemedicine. The role of the nutritionist in the nutritional consultation by videoconference had a degree of satisfaction higher than 70percen. 62.9percentof the respondents prefer the nutritional consultation to be combined. Only 50percent indicated that the zoom videoconferencing platform favors the nutritionist-patient relationship. The telemedicine nutritional consultation makes it possible to monitor the patient's nutritional status without the need to attend in person, which improves access to care. There is a high level of acceptance by patients who have received nutritional care via telemedicine(AU)

Docking and quantitative structure-activity relationship of bi-cyclic heteroaromatic pyridazinone and pyrazolone derivatives as phosphodiesterase 3A (PDE3A) inhibitors.

PDE3s belong to the phosphodiesterases family, where the PDE3A isoform is the major subtype in platelets involved in the cAMP regulation pathway of platelet aggregation. PDE3A inhibitors have been designed as potential antiplatelet agents. In this work, a homology model of PDE3A was developed and used to obtain the binding modes of bicyclic heteroaromatic pyridazinones and pyrazolones. Most of the studied compounds adopted similar orientations within the PDE3A active site, establishing hydrogen bonds with catalytic amino acids. Besides, the structure-activity relationship of the studied inhibitors was described by using a field-based 3D-QSAR method. Different structure alignment strategies were employed, including template-based and docking-based alignments. Adequate correlation models were obtained according to internal and external validations. In general, QSAR models revealed that steric and hydrophobic fields describe the different inhibitory activities of the compounds, where the hydrogen bond donor and acceptor fields have minor contributions. It should be stressed that structural elements of PDE3A inhibitors are reported here, through descriptions of their binding interactions and their differential affinities. In this sense, the present results could be useful in the future design of more specific and potent PDE3A inhibitors that may be used for the treatment of cardiovascular diseases.

Study of the interactions between Edaglitazone and Ciglitazone with PPARγ and their antiplatelet profile.

Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor with an important role in lipid metabolism, inflammation and cardiovascular diseases. PPARγ ligands have inhibitory effects on platelet aggregation via the cAMP pathway, which may confer them a protective cardioprotective role. Edaglitazone and Ciglitazone are two chemically-similar thiazolidinedione (TZD) drugs that have been described as potent PPARγ agonists; however, Edaglitazone is over 100 times more potent than Ciglitazone. Here, we report a computational study to describe the ligand binding and the experimental antiplatelet profiles of Edaglitazone and Ciglitazone. Both ligands presented similar orientations within the PPARγ binding site. Their polar heads exhibit complex hydrogen bond networks with the residues at arm I pocket, while their hydrophobic tails are oriented inside arm II or the entrance pocket. The bulkier and longer tail of Edaglitazone exhibited additional hydrophobic interactions, explaining its stronger binding to PPARγ supported by binding affinity calculations. On the other hand, both Edaglitazone and Ciglitazone displayed an antiplatelet activity, but only Edaglitazone retained such effect at low concentrations. Furthermore, we evidenced that Edaglitazone increases intraplatelet cAMP levels and prevents PPARγ secretion, explaining its greater antiplatelet activity. Altogether, the more potent PPARγ agonist Edaglitazone seems to be a potent antiplatelet agent.

Binding-affinity predictions of HSP90 in the D3R Grand Challenge 2015 with docking, MM/GBSA, QM/MM, and free-energy simulations.

We have estimated the binding affinity of three sets of ligands of the heat-shock protein 90 in the D3R grand challenge blind test competition. We have employed four different methods, based on five different crystal structures: first, we docked the ligands to the proteins with induced-fit docking with the Glide software and calculated binding affinities with three energy functions. Second, the docked structures were minimised in a continuum solvent and binding affinities were calculated with the MM/GBSA method (molecular mechanics combined with generalised Born and solvent-accessible surface area solvation). Third, the docked structures were re-optimised by combined quantum mechanics and molecular mechanics (QM/MM) calculations. Then, interaction energies were calculated with quantum mechanical calculations employing 970-1160 atoms in a continuum solvent, combined with energy corrections for dispersion, zero-point energy and entropy, ligand distortion, ligand solvation, and an increase of the basis set to quadruple-zeta quality. Fourth, relative binding affinities were estimated by free-energy simulations, using the multi-state Bennett acceptance-ratio approach. Unfortunately, the results were varying and rather poor, with only one calculation giving a correlation to the experimental affinities larger than 0.7, and with no consistent difference in the quality of the predictions from the various methods. For one set of ligands, the results could be strongly improved (after experimental data were revealed) if it was recognised that one of the ligands displaced one or two water molecules. For the other two sets, the problem is probably that the ligands bind in different modes than in the crystal structures employed or that the conformation of the ligand-binding site or the whole protein changes.

Performance of the MM/GBSA scoring using a binding site hydrogen bond network-based frame selection: the protein kinase case.

A conformational selection method, based on hydrogen bond (Hbond) network analysis, has been designed in order to rationalize the configurations sampled using molecular dynamics (MD), which are commonly used in the estimation of the relative binding free energy of ligands to macromolecules through the MM/GBSA or MM/PBSA method. This approach makes use of protein-ligand complexes obtained from X-ray crystallographic data, as well as from molecular docking calculations. The combination of several computational approaches, like long MD simulations on protein-ligand complexes, Hbond network-based selection by scripting techniques and finally MM/GBSA, provides better statistical correlations against experimental binding data than previous similar reported studies. This approach has been successfully applied in the ranking of several protein kinase inhibitors (CDK2, Aurora A and p38), which present both diverse and related chemical structures.