5-HT 7 Receptor Ligands: A 3D-QSAR CoMFA and CoMSIA Analysis of Quinazolinone Derivatives

TLDR: D-QSAR studies based on Comparative molecular field analysis ( CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were investigated on a series of 77 novel Quinazolinone derivatives as 5-HT7 receptor inhibitors producing very good results.

Abstract: D-QSAR studies based on Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were investigated on a series of 77 novel Quinazolinone derivatives as 5-HT7 receptor inhibitors. The best prediction was obtained with a CoMFA standard model (q 2 = 0.851, r 2 = 0.950) and with CoMSIA combined Steric, Electrostatic, Hydrophobic and Hydrogen bond donor and acceptor fields (q 2 = 0.850, r 2 = 0.945). Both models were validated by a test set of nineteen compounds producing very good results. The structural features like physiochemical properties of ligands which contribute positively towards Steric, Electrostatic, Hydrophobic and Hydrogen bond donor fields were analyzed with the help of contour maps generated by CoMFA and CoMSIA. The information obtained from CoMFA and CoMSIA 3-D contour maps can be used for the design of Quinazolinone based analogs as 5-HT7 receptor agents. In mammals, there are six classes of G protein-coupled 5- HT receptors, namely 5-HT1, 5-HT2, 5-HT4, 5-HT5, 5-HT6 and 5-HT7. Among them, 5-HT7 receptor was most recently cloned in 1993 and is found in the brain more specifically in the hypothalamus, thalamus, hippocampus, and cortex regions. The 5-HT7 receptor is a G-protein- coupled receptor (GPCR) protein and is found to stimulate cAMP production which activates the extracellular signal- regulated kinase (ERK) through a mechanism that is dependent on a Ras monomeric GTPase. 6