title: QSAR and pharmacophore analysis of a series of piperidinyl urea derivatives as HERG blockers and H3 antagonists.
abstract: In the present study, a computational based pharmacophore and structural analysis were performed on a series of piperidinyl urea derivatives, a limited number of compounds which have variation in structures and activities that exhibit hERG blocking and H3 antagonistic activities. The conducted QSAR studies demonstrated that the developed models are statistically significant, which have been confirmed through validation. The Q2 values for the models developed with hERG blocking activity are > 0.8 and with the H3 antagonistic activity are > 0.6. The descriptors contributed in the models show that the distributed polar properties on the vdW surface of the molecules are important for the hERG blocking activity. The vsurf_ descriptors (surface area, volume and shape) such as vsurf_DD13 and vsurf_Wp4 correlate with the H3 antagonistic activity of these compounds. The distances between the pharmacophore sites were measured in order to confirm their significance to the activities. The results reveal that the acceptor (acc), donor (don), hydrophobic (hyd) and aromatic/hydrophobic (aro/hyd) pharmacophore properties are favorable contours sites for both the activities. Also, our study reveals that the distance between the polar contours (acc, don, etc) has to be small for better hERG blocking activity. The distances between the aro/hyd to the polar groups should be higher for better hERG blocking activity. However, the H3 antagonistic activity for these series depends upon hydrophobic property of the molecules, particularly the hyd and the hyd/aro contours of the molecules. Hence, these results reveal the requirements on the structural properties and the distances between the pharmacophore contour sites of the molecules responsible for their hERG and H3 antagonistic activities.
authors.affiliation: REQUIMTE, Departamento de Quimica e Bioquimica, Faculdade de Ciencias, Universidade do Porto, 687, Rua do Campo Alegre, 4169-007 Porto, Portugal. hari.nmoorthy@gmail.com
authors.forename: N S Hari Narayana
authors.initials: NS
authors.lastname: Moorthy
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Ramos
authors.forename: Pedro A
authors.initials: PA
authors.lastname: Fernandes
mesh_terms: D003198:Computer Simulation; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D054828:Histamine H3 Antagonists / Q000737:chemistry* / Q000494:pharmacology; D008956:Models, Chemical; D026902:Potassium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D012984:Software; D014508:Urea / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D051638:Ether-A-Go-Go Potassium Channels; D054828:Histamine H3 Antagonists; D026902:Potassium Channel Blockers; D014508:Urea