The interactions of Met and Cys with other amino acid side chains have received little attention, in contrast to aromatic–aromatic, aromatic–aliphatic or/and aliphatic–aliphatic interactions. ...Precisely, these are the only amino acids that contain a sulfur atom, which is highly polarizable and, thus, likely to participate in strong Van der Waals interactions. Analysis of the interactions present in membrane protein crystal structures, together with the characterization of their strength in small‐molecule model systems at the ab‐initio level, predicts that Met–Met interactions are stronger than Met–Cys ≈ Met–Phe ≈ Cys–Phe interactions, stronger than Phe–Phe ≈ Phe–Leu interactions, stronger than the Met–Leu interaction, and stronger than Leu–Leu ≈ Cys–Leu interactions. These results show that sulfur‐containing amino acids form stronger interactions than aromatic or aliphatic amino acids. Thus, these amino acids may provide additional driving forces for maintaining the 3D structure of membrane proteins and may provide functional specificity.
Pungent chemical compounds originating from decaying tissue are strong drivers of animal behavior. Two of the best-characterized death smell components are putrescine (PUT) and cadaverine (CAD), ...foul-smelling molecules produced by decarboxylation of amino acids during decomposition. These volatile polyamines act as 'necromones', triggering avoidance or attractive responses, which are fundamental for the survival of a wide range of species. The few studies that have attempted to identify the cognate receptors for these molecules have suggested the involvement of the seven-helix trace amine-associated receptors (TAARs), localized in the olfactory epithelium. However, very little is known about the precise chemosensory receptors that sense these compounds in the majority of organisms and the molecular basis of their interactions. In this work, we have used computational strategies to characterize the binding between PUT and CAD with the TAAR6 and TAAR8 human receptors. Sequence analysis, homology modeling, docking and molecular dynamics studies suggest a tandem of negatively charged aspartates in the binding pocket of these receptors which are likely to be involved in the recognition of these small biogenic diamines.
Oxidative stress is the consequence of an abnormal increase of reactive oxygen species (ROS). ROS are generated mainly during the metabolism in both normal and pathological conditions as well as from ...exposure to xenobiotics. Xenobiotics can, on the one hand, disrupt molecular machinery involved in redox processes and, on the other hand, reduce the effectiveness of the antioxidant activity. Such dysregulation may lead to oxidative damage when combined with oxidative stress overpassing the cell capacity to detoxify ROS. In this work, a green fluorescent protein (GFP)-tagged nuclear factor erythroid 2-related factor 2 (NRF2)-regulated sulfiredoxin reporter (Srxn1-GFP) was used to measure the antioxidant response of HepG2 cells to a large series of drug and drug-like compounds (2230 compounds). These compounds were then classified as positive or negative depending on cellular response and distributed among different modeling groups to establish structure–activity relationship (SAR) models. A selection of models was used to prospectively predict oxidative stress induced by a new set of compounds subsequently experimentally tested to validate the model predictions. Altogether, this exercise exemplifies the different challenges of developing SAR models of a phenotypic cellular readout, model combination, chemical space selection, and results interpretation.
Highlights • 7TMRs contain a large number of sulfur–sulfur and sulfur–aromatic interactions. • Met and Cys residues of 7TMRs govern important signaling and functional events. • Met–arene interactions ...stabilize 7TMR states related to specific signaling pathways. • Met–arene interactions tune the orientation of functional aromatic residues.
Systematic halogenation of two native opioid peptides has shown that halogen atoms can modulate peptide–receptor interactions in different manners. First, halogens may produce a steric hindrance that ...reduces the binding of the peptide to the receptor. Second, chlorine, bromine, or iodine may improve peptide binding if their positive σ-hole forms a halogen bond interaction with negatively charged atoms of the protein. Lastly, the negative electrostatic potential of fluorine can interact with positively charged atoms of the protein to improve peptide binding.
The finding that ergotamine binds serotonin receptors in a less conserved extended binding pocket close to the extracellular entrance, in addition to the orthosteric site, allowed us to obtain 5-HT7R ...antagonist 6 endowed with high affinity (K i = 0.7 nM) and significant 5-HT1AR selectivity (ratio >1428). Compound 6 exhibits in vivo antidepressant-like effect (1 mg/kg, ip) mediated by the 5-HT7R, which reveals its interest as a putative research tool or pharmaceutical in depression disorders.
NMR assignment in regioisomeric hydroquinones Dobado, Jose A.; Gómez-Tamayo, José C.; Calvo-Flores, Francisco G. ...
Magnetic resonance in chemistry,
June 2011, Letnik:
49, Številka:
6
Journal Article
Background and purposeSpain has been heavily affected by COVID-19. Reallocation of resources for managing the outbreak might have caused a disruption in stroke care. This study analyses the impact on ...stroke care of reorganising the healthcare system in response to the first COVID-19 outbreak peak in Spain and the strategies adopted by Spanish stroke units to deal with this impact.Materials and methodsWe obtained data from a structured survey sent to the responsible of stroke units across the country. We recorded the number of strokes, stroke code activations, intravenous thrombolysis treatments and mechanical thrombectomies during February and March 2019 and 2020. We also collected information on the impact on workflow metrics and on the availability of specialised neurological care and rehabilitation treatments, the characteristics of stroke care for patients with SARS-CoV-2 infection and the impact on human resources. We compared the activity data between 2019 and 2020 and the information on activity and impact on stroke care between regions classified according to the disease incidence rate.ResultsFifty-seven (75%) of all stroke units in Spain responded to the survey. There was an overall reduction in admissions for all stroke types during the outbreak’s peak and in the number of stroke code activations and intravenous thrombolysis treatments, results that were independent of the COVID-19 incidence rate. Participants reported a delay in workflow metrics and a reduction of admissions to stroke units, outpatient clinics and rehabilitation therapies. Specific pathways and protocols for managing stroke patients with SARS-CoV-2 infection have been established.ConclusionThe COVID-19 outbreak has jeopardised all phases of stroke care. As a consequence, some patients with stroke did not receive adequate treatment.
Abstract Purpose Acute kidney injury (AKI) is a frequent complication after cardiac surgery and is associated with increased mortality. The aim was to design a nondialytic AKI score in patients with ...previously normal renal function undergoing cardiac surgery. Methods Data were collected on 909 patients who underwent cardiac surgery with cardiopulmonary bypass between 2012 and 2014. A total of 810 patients fulfilled the inclusion criteria. Patients were classified as having AKI based on the RIFLE criteria. Postoperative AKI occurred in 137 patients (16.9%). Several parameters were recorded preoperatively, intraoperatively, and at intensive care unit admission, looking for a univariate and multivariate association with AKI risk. A second data set of 741 patients, from 2 different hospitals, was recorded as a validation cohort. Results Four independent risk factors were included in the CRATE score: creatinine (odds ratio OR, 9.66; 95% confidence interval CI, 4.77-19.56; P < .001), EuroSCORE (OR, 1.40; CI, 1.29-1.52; P < .001), lactate (OR, 1.03; CI, 1.01-1.04; P < .001), and cardiopulmonary bypass time (OR, 1.01; CI, 1.01-1.02; P < .001). The accuracy of the model was good, with an area under the curve of 0.89 (CI, 0.85-0.92). The CRATE score retained good discrimination in validation cohort, with an area under the curve of 0.81 (95% CI, 0.78-0.85). Conclusions CRATE score is an accurate and easy to calculate risk score that uses affordable and widely available variables in the routine care surgical patients.
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