Procainamide [BSA]

DNA methyltransferases (DNMTs) are involved in epigenetic regulation of the genome and are promising targets for therapeutic intervention in cancer and other diseases. Until now, very limited information is available concerning the molecular dynamics of DNMTs. The natural product nanaomycin A is the first selective inhibitor of DNMT3B that induce genomic demethylation. Herein we report long (>100 ns) molecular dynamics simulations for human DNMT3B bound to nanaomycin A with and without the presence of the cofactor S-adenosyl-L-methionine (SAM). We concluded that SAM favors the binding of nanaomycin A to DNMT3B. Key interactions of nanaomycin A with DNMT3B involve long lasting interactions with Arg731, Arg733, Arg832, and the catalytic Cys651. Results further support the previous hypothesis that nanaomycin A has key interactions with amino acid residues involved in the mechanism of methylation. This work represents one of the first molecular dynamics studies of DNMT3B. Results of this work shed light on the structure and binding recognition process of a key epigenetic enzyme with a small molecule inhibitor. (C) 2011 Elsevier Inc. All rights reserved.

Background: Procainamide is known to prolong PR, QRS, and QTc intervals in adults and is utilized to unmask the distinct electrocardiographic signatures, including right bundle branch block pattern and right precordial ST segment elevation seen with Brugada syndrome. This study analyzes a pediatric case series of procainamide challenges done to evaluate for possible Brugada syndrome. Our goal was to quantify the impact of procainamide on electrocardiographic intervals in all pediatric patients, regardless of the eventual determination of Brugada syndrome status. Methods: We retrospectively reviewed all children undergoing procainamide challenge, consecutively from March 2009 to September 2012. Patients received intravenous procainamide over 15 minutes. All electrocardiograms (ECGs) performed during the drug challenge were reviewed. Analysis and ECG measurements were performed by investigators blinded to clinical diagnoses. Results: All patients undergoing procainamide infusion had prolongation of their PR (mean +14%; 0-45%), QRS (+13%; 2-49%), and QTc (+15%; 4-30%) intervals regardless of testing outcome. QTc prolongation to >460 ms following procainamide infusion occurred in 76% of patients. No sustained arrhythmias or adverse events occurred. Conclusions: ECG changes including prolongation of the PR, QRS, and QTc intervals were seen in all children who underwent procainamide challenge for evaluation of possible Brugada syndrome. An increase in the PR, QRS, and QTc intervals of at least 20% occurred in all children without any adverse events. The QTc prolongation was not completely explained by the QRS prolongation.