Bell-Evans model and steered molecular dynamics in uncovering the dissociation kinetics of ligands targeting G-protein-coupled receptors

Recently, academic and industrial scientific communities involved in kinetics-based drug development have become immensely interested in predicting the drug target residence time. Screening drug candidates in terms of their computationally predicted residence times, which is a measure of drug efficacy in vivo, and simultaneously assessing computational binding affinities are becoming inevitable. Non-equilibrium molecular simulation approaches are proven to be useful in this purpose. Here, we have implemented an optimized approach of combining the data derived from steered molecular dynamics simulations and the Bell-Evans model to predict the absolute residence times of the antagonist ZMA241385 and agonist NECA that target the A2A adenosine receptor of the G-protein-coupled receptor (GPCR) protein family. We have predicted the absolute ligand residence times on the timescale of seconds. However, our predictions were many folds shorter than those determined experimentally. Additionally, we calculated the thermodynamics of ligand binding in terms of ligand binding energies and the per-residue contribution of the receptor. Subsequently, binding pocket hotspot residues that would be important for further computational mutagenesis studies were identified. In the experiment, similar sets of residues were found to be in significant contact with both ligands under study. Our results build a strong foundation for further improvement of our approach by rationalizing the kinetics of ligand unbinding with the thermodynamics of ligand binding

Time Series Analysis on the Conformational Change of c-Src Tyrosine Kinase

c-Src tyrosine kinase plays an important role in signal transduction pathways, where its activity is regulated by phosphorylation of the two tyrosine residues. We performed targeted molecular dynamics simulation to obtain trajectory of conformational change from inactive to active form. To investigate the conformational change of c-Src tyrosine kinase, we applied network analysis to time series of correlation among residues. The time series of correlation between residues during the conformational change generated by targeted molecular dynamic simulation. With centrality measures such as betweenness centrality, degree centrality, and closeness centrality, we observed a few important residues that significantly contribute to the conformational change of c-Src tyrosine kinase for the different time steps

Congenital Syphilis Presenting with a Generalized Bullous and Pustular Eruption in a Premature Newborn

Congenital syphilis occurs when Treponema pallidum crosses the placenta during pregnancy or from contact with an infectious genital lesion during delivery. Cutaneous manifestations of congenital syphilis are relatively common, occurring in approximately 30% to 70% of patients. Maculopapular lesions, vesiculobullous lesions, condylomata lata lesions, annular lesions, and erythema multiforme-like targetoid lesions have been reported. We report on a premature newborn with congenital syphilis who presented with generalized bullous and pustular eruption and desquamation at birth

Korean Patients with Superwarfarin Intoxication and Their Outcome

This observational study aimed at evaluating recent superwarfarin intoxication of Korean patients. Ten patients were diagnosed as or highly suspicious for superwarfarin intoxication. Case report forms described by attending hematologists of the patients were collected and analyzed. Bleeding symptoms were varied among the patients. Patients uniformly showed prolonged prothrombin time (PT) and activated thromboplastin time (aPTT) with decreased activity of vitamin K dependent coagulation factors. Positive serum brodifacoum test results in 4 of 5 requested patients contributed to confirmatory diagnosis. Psychiatric interview revealed an attempted ingestion in one patient. High dose vitamin K1 therapy promptly corrected prolonged PT and aPTT, but hasty discontinuation caused repeated bleeding diathesis in 6 patients. Route of intoxication was unknown or not definite among 8 of 10 patients. Three patients had a possibility of environmental exposure considering their occupations: there might be intoxication by transdermal absorption or inhalation. Therefore, high dose and prolonged use of vitamin K1 therapy is necessary for effective detoxification. Further detailed investigation on environmental exposure and efforts to improve availability of the blood level test in clinic are requested

Feasibility of the Radial Artery as a Vascular Access Route in Performing Primary Percutaneous Coronary Intervention

We aimed to evaluate the feasibility of transradial primary percutaneous coronary intervention (PCI) in patients with ST elevation myocardial infarction (STEMI) by comparing the procedural results and complications with those of transfemoral intervention. From April 1997 to October 2004, we enrolled 352 consecutive cases of STEMI who underwent primary PCI. The femoral route was used in 132 cases (TFI group) and the radial route was used in 220 cases (TRI group). Cases with Killips class IV, a negative Allen test or a non-palpable radial artery were excluded from our study. Baseline clinical and angiographic profiles were comparable in both groups. Vascular access time was 3.8 ± 3.5 min in the TFI group and 3.6 ± 3.1 min in the TRI group, and cath room to reperfusion time was 25 ± 11 min in the TRI group and 26 ± 13 min in the TRI group. The procedural success rate was 89% in the TFI group and 88% in the TRI group. Crossover occurred in 9 cases (4%) due to approaching vessel tortuosity in the TRI group. Major access site complications occurred in 7 cases (5%) in the TFI group, and there were no complications in the TRI group (p < 0.001). Although radial occlusion occurred in 5 cases of the TRI group, there was no evidence of hand ischemia. The total hospital stay was significantly shorter in TRI group than in TFI group. In conclusion, use of the radial artery might be a potential vascular access route in performing primary PCI in selected cases