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Online Journal of Bioinformatics ©
Volume 12(2):357-370, 2011.
Sachidanand Singh, Atul Kumar, J. Jannet Vennila
Department of Bioinformatics, School of Biotechnology and Health Sciences, Karunya U niversity, Coimbatore, Tamil Nadu, India
Singh S, Kumar A, Vennila JJ., Analysis of inhibitory activity of 2, 4-diamino-5-methyl-5-deazapteridine (DMDP) derivatives against recombinant human dihydrofolate reductase by molecular modeling, Onl J Bioinform., 12(2):357-370, 2011. The indispensable role of folate metabolism in the biosynthesis of nucleic acid precursors acts as an attractive target for Rheumatoid Arthritis (RA) treatment. 2,4-diamino-5-methyl-5-deazapteridine (DMDP) analogues have been designed and their molecular interactions and binding affinities with human dihydrofolate reductase (DHFR) protein (1DHF) have been studied using docking-molecular mechanics. A new shape-based method, Glide 4.0, was used for docking DMDP derivatives into DHFR active sites. The binding free energies of these compounds to human DHFR were found to have a good correlation (r2= 0.7216) with the experimental inhibitory activities. The glide energy was validated by calculating energy of binding by MM-GBSA solvation model and for both the cases the r2 was in the range of 0.7949 indicating good data ﬁt. The results provide the most favorable binding mode of the top ranking compounds which will be useful in designing new DMDP derivatives as human DHFR inhibitors.
Keyword: Rheumatoid Arthritis, DMDP, DHFR, GLIDE, MMGBSA