3D QSAR based design of novel oxindole derivative as 5HT₇ inhibitors

Abstract

To understand the structural requirements of 5-hydroxytryptamine (5HT₇) receptor inhibitors and to design new ligands against 5HT₇ receptor with enhanced inhibitory potency, a three-dimensional quantitative structure–activity relationship study with comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) for a data set of 56 molecules consisting of oxindole, tetrahydronaphthalene, aryl ketone substituted arylpiperazinealkylamide derivatives was performed. Derived model showed good statistical reliability in terms of predicting 5HT₇ inhibitory activity of the molecules, based on molecular property fields like steric, electrostatic, hydrophobic, hydrogen bond donor and hydrogen bond acceptor fields. This is evident from statistical parameters like conventional r² and a cross validated (q²) values of 0.985, 0.743 for CoMFA and 0.970, 0.608 for CoMSIA, respectively. Predictive ability of the models to determine 5HT₇ antagonistic activity is validated using a test set of 16 molecules that were not included in the training set. Predictive r² obtained for the test set was 0.560 and 0.619 for CoMFA and CoMSIA, respectively. Steric, electrostatic fields majorly contributed toward activity which forms the basis for design of new molecules. Absorption, distribution, metabolism and elimination (ADME) calculation using QikProp 2.5 (Schrodinger 2010, Portland, OR) reveals that the molecules confer to Lipinski’s rule of five in majority of the cases.

• 5-hydroxytryptamine
• antidepressants
• comparative molecular field analysis
• comparative molecular similarity indices analysis
• G protein coupled receptor
• oxindole derivatives
• three-dimensional quantitative structure–activity relationship

Acknowledgements

The authors are thankful to the Department of Chemistry, Nizam College, Hyderabad, India where the research was carried out. The authors also acknowledge Schrödinger Inc. for GLIDE software, Tripos Inc. for SYBYLX-1.2.