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OJBTM
Online Journal of Bioinformatics ©
Volume 12(2):357-370, 2011.
Analysis of inhibitory activity of 2, 4-diamino-5-methyl-5-deazapteridine (DMDP) derivatives against recombinant human dihydrofolate reductase by molecular modeling.
Sachidanand Singh, Atul Kumar, J. Jannet Vennila
Department of
Bioinformatics, School of Biotechnology and Health Sciences, Karunya U niversity, Coimbatore, Tamil Nadu, India
ABSTRACT
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
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