QSAR and pharmacophore analysis of a series of piperidinyl urea derivatives as hERG blockers and H3 antagonists

• Type: Article in International Scientific Journal
• Date: 2013

Authors

Moorthy, NSHN (Author) Other; Ramos, MJ (Author) FCUP; Fernandes, PA (Author) FCUP

Journal

Title: Current Drug Discovery Technologies

Vol. 10

Pages: 47-58

ISSN: 1570-1638

Publisher: Bentham Science

Indexing

ISI Web of Knowledge

Scopus - 7 Citations

Other information

Authenticus ID: P-008-A0R

Abstract (EN): 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. © 2013 Bentham Science Publishers.

Language: English

Type (Professor's evaluation): Scientific

No. of pages: 12