Exploring QSTR and toxicophore of hERG K+ channel blockers using GFA and HypoGen techniques

Computational Methods in Drug Discovery

“…It has been estimated that 2-3% of prescribed medications include some unintended QT elongation (Recanatini et al, 2005). Although most drugs have been shown to inhibit the rapid component of the outward potassium current (Garg et al, 2008), interaction between drugs and hERG is not completely understood, and high-affinity ligands tend to interact with the inactivated channel with low voltagedependency, whereas low-affinity ligands tend to interact with the activated state with high voltagedependent kinetics (Ficker et al, 2002). However, key residues involved in the interaction between hERG and at least some ligands have been identified.…”

“…A two-stage approach using two optimized models yielded a prediction accuracy of 76-81% (Nisius and Goller, 2009). Garg et al (2008) used a genetic function approximation to generate quantitative structure-toxicity relationship (QSTR) models using 2D descriptors generated using the QSAR+ module of Cerius (Accelrys). These models were trained with 56 hERG blockers and descriptors included electrotopological descriptors that contained information regarding the topological environments for all atoms in the molecule as well as electronic interactions with other atoms in the molecule.…”

Molecular Docking Guided Comparative GFA, G/PLS, SVM and ANN Models of Structurally Diverse Dual Binding Site Acetylcholinesterase Inhibitors

“…QSAR is one of the most important areas in chemoinformatics, and its advances have widened the scope of rational drug design and the search for the mechanism of drug action. [10][11][12][13] It is a well-established fact that the chemical and pharmacological effects of a comAbstract: Recently discovered 42 AChE inhibitors binding at the catalytic and peripheral anionic site were identified on the basis of molecular docking approach, and its comparative quantitative structure-activity relationship (QSAR) models were developed. These structurally diverse inhibitors were obtained by our previously reported highthroughput in vitro screening technique using 384-well plate's assay based on colorimetric method of Ellman.…”

Comparative Effects of Liensinine and Neferine on the Human Ether-a-go-go-related Gene Potassium Channel and Pharmacological Activity Analysis

“…Published pharmacophore models of hERG channel blockers typically have three important chemical features, (a) hydrophobic group, (b) ring aromatic group, and (c) hydrogen bond acceptor lipid group [28][29][30], where hydrophobic nature is a key factor effecting on drugs crossing the cell membrane and accessing the channel from the cell interior. To study the antiarrhythmic QSAR of liensinine derivatives, six derivatives were synthesized via acylation and etherification on its two phenol hydroxyl groups.…”