Binding mode analysis of 2,4-diamino-5-methyl-5-deaza-6-substituted pteridines with Mycobacterium tuberculosis and human dihydrofolate reductases

被引:44
作者
da Cunha, Elaine F. F. [1 ]
Ramalho, Teodorico C. [1 ]
Reynolds, Robert C. [2 ,3 ]
机构
[1] Univ Fed Lavras UFLA, Dept Quim, BR-37200000 Lavras, MG, Brazil
[2] So Res Inst, Drug Discovery Div, Birmingham, AL 35255 USA
[3] So Res Inst, Drug Dev Div, Birmingham, AL 35255 USA
关键词
D O I
10.1080/07391102.2008.10507186
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
There are major differences between the structures of human dihydrofolate reductase (hD-HFR) and Mycobacterium tuberculosis dihydrofolate reductase (mtDHFR). These differences may allow the design of more selective mtDHFR inhibitors. In this paper, we have used docking approaches to study the binding orientations and predict binding affinities of 2,4-diamino-5-methyl-5-deazapteridines derivatives in both hDHFR and mtDHFR. Our results of molecular docking combined with experimental data for inhibition of the human and mycobacterial dihydrofolate reductases suggest the presence of empty spaces around the 2,4-diaminodeazapteridine and N-10-phenyl rings in the mtDHFR active site that are not found in the hDHFR-bound structures. Preparation of new analogs with substituents attached to C7 of the pteridine nucleus and positions 3 and 4 of the N-10-phenyl group should increase the affinity and selectivity for mtDHFR.
引用
收藏
页码:377 / 385
页数:9
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