Ahmed S Abdelkhalek1, Faik N Musayev1,2, Kavita A Iyer1, Prithvi Hemanth1, Martin K Safo1,2, Małgorzata Dukat1. 1. Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA. 2. The Institute for Structural Biology, Drug Discovery and Development School of Pharmacy, Virginia Commonwealth University, Richmond, VA 23298, USA.
Abstract
Certain 2-amino-3,4-dihydroquinazolines bind at 5-HT3 serotonin receptors and act as antagonists (e.g. 6-chloro) whereas others bind with little to no affinity and lack functional activity (e.g. 8-chloro). The purpose of this investigation was to gain insight as to why this might be the case. X-Ray crystallographic studies revealed that the N-C-N distances in the examined analogs are nearly identical (1.31 - 1.34 Å), suggesting that differences in N-C-N delocalization does not account for differences in affinity/action. Homology modeling hydrophatic interactions (HINT) analysis revealed that the 6-chloro analog formed a greater number, and more favorable, interactions with the receptor, whereas the 8-chloro analog formed fewer, and unfavorable, interactions. The affinity and activity of the 6-chloro quinazoline relative to its 8-chloro counterpart are unrelated to the N-C-N delocalization pattern but might be related to specific (favorable and unfavorable) interactions of quinazoline substituents with certain receptor features as determined by HINT analysis.
Certain 2-amino-3,4-dihydroquinazolines bind at n class="Gene">5-HT3 serotonin receptors and act as antagonists (e.g. 6-chloro) whereas others bind with little to no affinity and lack functional activity (e.g. 8-chloro). The purpose of this investigation was to gain insight as to why this might be the case. X-Ray crystallographic studies revealed that the N-C-N distances in the examined analogs are nearly identical (1.31 - 1.34 Å), suggesting that differences in N-C-N delocalization does not account for differences in affinity/action. Homology modeling hydrophatic interactions (HINT) analysis revealed that the 6-chloro analog formed a greater number, and more favorable, interactions with the receptor, whereas the 8-chloro analog formed fewer, and unfavorable, interactions. The affinity and activity of the 6-chloro quinazoline relative to its 8-chloro counterpart are unrelated to the N-C-N delocalization pattern but might be related to specific (favorable and unfavorable) interactions of quinazoline substituents with certain receptor features as determined by HINT analysis.
Entities:
Keywords:
3D Homology modeling; 5-HT3 receptors; Cyclic guanidines; Dihydroquinazolines; HINT analysis; X-Ray crystallography
Authors: Ahmed S Abdelkhalek; Genevieve S Alley; Osama I Alwassil; Shailesh Khatri; Philip D Mosier; Heather L Nyce; Michael M White; Marvin K Schulte; Małgorzata Dukat Journal: ACS Chem Neurosci Date: 2018-11-08 Impact factor: 4.418
Authors: Luc J Bourhis; Oleg V Dolomanov; Richard J Gildea; Judith A K Howard; Horst Puschmann Journal: Acta Crystallogr A Found Adv Date: 2015-01-01 Impact factor: 2.290