title: Analysis of van der Waals surface area properties for human ether-a-go-go-related gene blocking activity: computational study on structurally diverse compounds.
abstract: In the present investigation, a computational analysis was performed on a data set comprised of human ether-a-go-go-related gene (hERG) blockers (triethanolamine, 1,3-thiazol-2-yl and tetrasubstituted imidazoline derivatives) in order to investigate the structural features required to reduce the hERG-induced cardiotoxicity problems in an early stage of drug discovery. The results derived from the quantitative structure-activity relationship (QSAR) analysis showed that the volume, surface area and shape descriptors (vsurf_) contributed significantly in all the models. This reveals that the hydrogen-bonding and hydrophilicity properties (vsurf_HB1, vsurf_CW4 and a_acc) on the van der Waals (vdW) surface of the molecule is negatively contributed for the hERG blocking activity and the hydrophobic property (vsurf_D6) and the total polar volume (vsurf_Wp2) on the vdW surface of the molecule are favourable for the activity. Further, the pharmacophore analysis also shows that the Aro/Hyd/Acc contour is one of the important biophore sites for the hERG blocking activity. This suggests that the presence of aromatic, hydrophobic and hydrogen-bonding groups in the molecules is favourable for interaction. In comparison with our earlier works (explaining the role of topological and hydrophobicity properties for the hERG blocking activity), these studies provided additional information on the importance of vdW surface area properties for the hERG blocking activity. These results can be used with other molecular modelling studies for the design of novel molecules that are free of cardiotoxicity.
authors.affiliation: Requimte, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal. hari.moorthy@fc.up.pt
authors.forename: N S H N
authors.initials: NS
authors.lastname: Moorthy
authors.forename: M J
authors.initials: MJ
authors.lastname: Ramos
authors.forename: P A
authors.initials: PA
authors.lastname: Fernandes
mesh_terms: D003198:Computer Simulation; D055808:Drug Discovery / Q000379:methods; D000072237:ERG1 Potassium Channel; D004983:Ethanolamines / Q000737:chemistry / Q000494:pharmacology; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D006801:Humans; D048288:Imidazolines / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
chemical_list: D000072237:ERG1 Potassium Channel; D004983:Ethanolamines; D051638:Ether-A-Go-Go Potassium Channels; D048288:Imidazolines; C000606913:KCNH2 protein, human; D026902:Potassium Channel Blockers; C009546:triethanolamine