DNA methyltransferases (DNMTs) are a family of enzymes that methylate DNA at the 
C5 position of cytosine residues, and their inhibition is a promising strategy 
for the treatment of various developmental and proliferative diseases, 
particularly cancers. In the present study, a binding model for hydralazine, 
with a validated homology model of human DNMT, was developed by the use of 
automated molecular docking and molecular dynamics simulations. The docking 
protocol was validated by predicting the binding mode of 2'-deoxycytidine, 
5-azacytidine, and 5-aza-2'-deoxycytidine. The inhibitory activity of 
hydralazine toward DNMT may be rationalized at the molecular level by similar 
interactions within the binding pocket (e.g., by a similar pharmacophore) as 
established by substrate-like deoxycytidine analogues. These interactions 
involve a complex network of hydrogen bonds with arginine and glutamic acid 
residues that also play a major role in the mechanism of DNA methylation. 
Despite the different scaffolds of other non-nucleoside DNMT inhibitors such as 
procaine and procainamide, the current modeling work reveals that these drugs 
exhibit similar interactions within the DNMT1 binding site. These findings are 
valuable in guiding the rational design and virtual screening of novel DNMT 
inhibitors.