ABSTRACT
SUMMARY: Molecular-similarity searches based on two-dimensional (2D) fingerprint and three-dimensional (3D) shape represent two widely used ligand-based virtual screening (VS) methods in computer-aided drug design. 2D fingerprint-based VS utilizes the binary fragment information on a known ligand, whereas 3D shape-based VS takes advantage of geometric information for predefined features from a 3D conformation. Given their different advantages, it would be desirable to hybridize 2D fingerprint and 3D shape molecular-similarity approaches in drug discovery. Here, we presented a general hybrid molecular-similarity protocol, referred to as HybridSim, obtained by combining the 2D fingerprint- and 3D shape-based similarity search methods and evaluated its performance on 595,036 actives and decoys for 40 pharmaceutically relevant targets available in the Directory of Useful Decoys Enhanced (DUD-E). Our results showed that HybridSim significantly improved the overall performance in 40 VS projects as compared with using only 2D fingerprint and 3D shape methods. Furthermore, HybridSim-VS, the first online platform using the proposed HybridSim method coupled with 17,839,945 screenable and purchasable compounds, was developed to provide large-scale and proficient VS capabilities to experts and nonexperts in the field. AVAILABILITY AND IMPLEMENTATION: HybridSim-VS web server is freely available at http://www.rcidm.org/HybridSim-VS/. CONTACT: lingwang@scut.edu.cn. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
Subject(s)
Drug Design , Software , Drug Evaluation, Preclinical/methods , Internet , Ligands , Molecular ConformationABSTRACT
Ischemia/reperfusion (I/R) induces prolongation of QT interval and action potential duration (APD), which is a major cardiac electrical disorder in patients with arrhythmias. However, the mechanism of QT interval prolongation induced by I/R remains unclear. In the present study, we hypothesized that the rapid component of delayed rectifier potassium (IKr) channel plays an important role in I/R-induced QT interval prolongation. We observed a marked attenuation of IKr and a significant prolongation of action potential duration (APD) in a simulated I/R system with sodium dithionite (Na2S2O4) in ventricular myocytes of guinea pigs. The IKr current density was inhibited by 64% and APD increased by 87% respectively. Moreover, the inhibition of IKr is primarily ascribed to overproduction of reactive oxygen species (ROS) by I/R, which can be partly reversed by antioxidant vitamin E (100µmol/L). The value of IKr tail current density increased from 0.516±0.040 pA/pF in I/R to 0.939±0.091 pA/pF when treated with vitamin E. Moreover, we also demonstrated that QTc interval was increased by I/R and reversed by Vitamin E in isolated guinea pig hearts. In conclusion, the inhibition of IKr is one of the underlying mechanisms of prolongation of QT interval and APD in I/R. Vitamin E might have a benefit in coronary reperfusion therapy.
Subject(s)
ERG1 Potassium Channel/antagonists & inhibitors , Long QT Syndrome/drug therapy , Long QT Syndrome/physiopathology , Myocardial Reperfusion Injury/prevention & control , Myocytes, Cardiac/drug effects , Vitamin E/pharmacology , Action Potentials/drug effects , Animals , Cells, Cultured , Disease Models, Animal , ERG1 Potassium Channel/metabolism , Electrocardiography , Guinea Pigs , Male , Myocardial Reperfusion Injury/metabolism , Myocytes, Cardiac/cytology , Myocytes, Cardiac/metabolism , SulfatesABSTRACT
A series of novel chalcone-rivastigmine hybrids were designed, synthesized, and tested in vitro for their ability to inhibit human acetylcholinesterase and butyrylcholinesterase. Most of the target compounds showed hBChE selective activity in the micro- and submicromolar ranges. The most potent compound 3 exhibited comparable IC50 to the commercially available drug (rivastigmine). To better understand their structure activity relationships (SAR) and mechanisms of enzyme-inhibitor interactions, kinetic and molecular modeling studies including molecular docking and molecular dynamics (MD) simulations were carried out. Furthermore, compound 3 blocks the formation of reactive oxygen species (ROS) in SH-SY5Y cells and shows the required druggability and low cytotoxicity, suggesting this hybrid is a promising multifunctional drug candidate for Alzheimer's disease (AD) treatment.
