title: Design of novel quinazolinone derivatives as inhibitors for 5HT7 receptor.
abstract: To study the pharmacophore properties of quinazolinone derivatives as 5HT(7) inhibitors, 3D QSAR methodologies, namely Comparative Molecular Field Analysis (CoMFA) and Comparative Molecular Similarity Indices Analysis (CoMSIA) were applied, partial least square (PLS) analysis was performed and QSAR models were generated. The derived model showed good statistical reliability in terms of predicting the 5HT(7) inhibitory activity of the quinazolione derivative, based on molecular property fields like steric, electrostatic, hydrophobic, hydrogen bond donor and hydrogen bond acceptor fields. This is evident from statistical parameters like q(2) (cross validated correlation coefficient) of 0.642, 0.602 and r(2) (conventional correlation coefficient) of 0.937, 0.908 for CoMFA and CoMSIA respectively. The predictive ability of the models to determine 5HT(7) antagonistic activity is validated using a test set of 26 molecules that were not included in the training set and the predictive r(2) obtained for the test set was 0.512 & 0.541. Further, the results of the derived model are illustrated by means of contour maps, which give an insight into the interaction of the drug with the receptor. The molecular fields so obtained served as the basis for the design of twenty new ligands. In addition, ADME (Adsorption, Distribution, Metabolism and Elimination) have been calculated in order to predict the relevant pharmaceutical properties, and the results are in conformity with required drug like properties.
authors.affiliation: Molecular Modeling and Medicinal Chemistry Group, Department of Chemistry, Nizam College, Osmania University, Basheerbagh, Hyderabad, India.
authors.forename: Aparna
authors.initials: A
authors.lastname: Chitta
authors.forename: Mohan Babu
authors.initials: MB
authors.lastname: Jatavath
authors.forename: Sabiha
authors.initials: S
authors.lastname: Fatima
authors.forename: Vijjulatha
authors.initials: V
authors.lastname: Manga
mesh_terms: D000928:Antidepressive Agents / Q000494:pharmacology; D015195:Drug Design; D057809:HEK293 Cells; D006801:Humans; D006860:Hydrogen Bonding; D057927:Hydrophobic and Hydrophilic Interactions; D020128:Inhibitory Concentration 50; D016018:Least-Squares Analysis; D008024:Ligands; D008958:Models, Molecular; D008968:Molecular Conformation; D021281:Quantitative Structure-Activity Relationship; D052999:Quinazolinones / Q000494:pharmacology*; D043562:Receptors, G-Protein-Coupled / Q000187:drug effects / Q000378:metabolism; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D015203:Reproducibility of Results; D055672:Static Electricity
chemical_list: D000928:Antidepressive Agents; D008024:Ligands; D052999:Quinazolinones; D043562:Receptors, G-Protein-Coupled; D011985:Receptors, Serotonin