Document Detail


Generation of Pharmacophore and Atom Based 3D-QSAR Model of Novel Isoquinolin-1-one and Quinazolin-4-one-type Inhibitors of TNFα
MedLine Citation:
PMID:  22530913     Owner:  NLM     Status:  Publisher    
Abstract/OtherAbstract:
In the present report, 3D-QSAR analysis was executed on the previously synthesized and evaluated derivatives of isoquinolin-1-ones and quinazolin-4-ones; potent inhibitors of tumor necrosis factor α (TNFα). Statistically significant 3D-QSAR models were generated using 42 molecules in the training set. The predictive ability of models was determined using a randomly chosen test set of 16 molecules, which gave excellent predictive correlation coefficients for 3-D models, suggesting good predictive index. Pharmacophore prediction generated a five point pharmacophore (AAHRR): two hydrogen bond acceptor (A), one hydrophobic (H) and two ring (RR) features. This pharmacophore hypothesis furnished a statistically meaningful 3D-QSAR model with partial least-square (PLS) factors seven having R2 = 0.9965, Q2 = 0.6185, Root Mean Squared Error = 0.4284 and Pearson-R = 0.853. Docking study revealed the important amino acid residues (His 15, Tyr 59, Tyr 151, Gly 121 and Gly 122) in the active site of TNFα that are involved in binding of the active ligand. Orientation of the pharmacophore hypothesis AAHRR.25 corresponded very closely with the binding mode recorded in the active site of ligand bound complex. The results of ligand based pharmacophore hypothesis and atom based 3D-QSAR furnished crucial structural insights and also highlighted the important binding features of isoquinolin-1-ones and quinazolin-4-ones derivatives, which may provide guidance for the rational design of novel and more potent TNFα inhibitors.
Authors:
Pradeep Hanumanthappa; Mahesh K Teli; Rajanikant G Krishnamurthy
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-4-24
Journal Detail:
Title:  Medicinal chemistry (Shariqah (United Arab Emirates))     Volume:  -     ISSN:  1875-6638     ISO Abbreviation:  -     Publication Date:  2012 Apr 
Date Detail:
Created Date:  2012-4-25     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  101240303     Medline TA:  Med Chem     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Affiliation:
School of Biotechnology, National Institute of Technology Calicut, Calicut - 673601, Kerala, India. rajanikant@nitc.ac.in.
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