3D-QSAR studies on the inhibitory activity of trimethoprim analogues against Escherichia coli dihydrofolate reductase.
Three-dimensional quantitative structure activity relationship (3D-QSAR) study has been carried out on the Escherichia coli DHFR inhibitors 2,4-diamino-5-(substituted-benzyl)pyrimidine derivatives to understand the structural features responsible for the improved potency. To construct highly predictive 3D-QSAR models, comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were used. The predicted models show statistically significant cross-validated and non-cross-validated correlation coefficient of r2 CV and r2 nCV, respectively. The final 3D-QSAR models were validated using structurally diverse test set compounds. Analysis of the contour maps generated from CoMFA and CoMSIA methods reveals that the substitution of electronegative groups at the first and second position along with electropositive group at the third position of R2 substitution significantly increases the potency of the derivatives. The results obtained from the CoMFA and CoMSIA study delineate the substituents on the trimethoprim analogues responsible for the enhanced potency and also provide valuable directions for the design of new trimethoprim analogues with improved affinity.
Chemical Laboratory, Central Leather Research Institute, Council of Scientific and Industrial Research, Adyar, Chennai 600 020, India.
Ramadoss
R
Vijayaraj
Mekapothula Lakshmi Vasavi
ML
Devi
Venkatesan
V
Subramanian
Pratim Kumar
PK
Chattaraj
D004926:Escherichia coli / Q000201:enzymology*; D005493:Folic Acid Antagonists / Q000138:chemical synthesis / Q000737:chemistry*; D007700:Kinetics; D016014:Linear Models; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry* / Q000378:metabolism; D014295:Trimethoprim / Q000031:analogs & derivatives* / Q000138:chemical synthesis
D005493:Folic Acid Antagonists; D014295:Trimethoprim; D013762:Tetrahydrofolate Dehydrogenase