Computational Studies of 1-Hydrazinophthalazine (Hydralazine) as Antineoplasic Agent. Docking Studies on Methyltransferase

Abstract

Hydralazine is a drug used as anti-hypertensive, and recently reported to be a DNA methylation inhibitor able to demethylate and reactivate the expression of tumor suppressor genes in cancer. The aim of the present study was to explore the potential mechanism by which hydralazine inhibits DNA methylation. For this purpose, we assessed the structural and electronic properties between 1-hydrazinophthalazine (hydralazine) and a putative ligand methyltransferase.

Molecular Modeling and Molecular Dynamics Studies of Hydralazine with Human DNA Methyltransferase 1

“…In a previous docking study of hydralazine with DNMT1, only the hydrazine form was considered. [28] In the present work, we docked both tautomeric forms within the catalytic site of DNMT1 in order to define a more precise role for the four nitrogen atoms in binding, and to identify potential sites of substitution to enhance the activity of hydralazine. The details of the docking results are summarized in Table 1.…”

“…[27] To gain insight into the binding mode and interactions of hydralazine and other inhibitors described above with DNMT1, and to consequently improve the development of novel inhibitors, we describe herein a study of the docking and molecular dynamics (MD) simulations of hydralazine with DNMT1. Although a binding model of hydralazine with DNMT1 was proposed in a previous study, [28] it was neither compared with the binding mode of 5-azacytidine and its analogues and other non-nucleoside inhibitors, nor did it provide a mechanistic interpretation of the inhibitory activity of hydralazine. In this work, we extend our previous docking studies by modeling the two possible tautomeric forms of hydralazine with a previously validated homology model of DNMT1.…”

A phase I study of hydralazine to demethylate and reactivate the expression of tumor suppressor genes

“…Its DNA demethylating activity can be explained by the interaction between its Nitrogen atoms with residues Lys162 and Arg240 of the DNA methyltransferase active site as showed in a silico model [27]. Hydralazine is a well-tolerated drug devoid of the common side effects of cytotoxic chemotherapy agents, however, its hypotensive effects could limit its use in a clinical setting, we thus felt desirable to determine the dose at which its demethylating activities were observed in a set of genes known to be methylated in cervical cancer.…”

The Importance of Aberrant DNA Methylation in Cancer

“…In lung cancer, these drugs induce demethylation of WIF-1 (Wnt Inhibitory Factor) promoter, a negative regulator of the Wnt-signaling pathway (Gao et al, 2009). -Hydralazine: The methylation inhibitory role was shown to be specifically related to the inhibition of DNMT (Angeles et al, 2005). Its combination with magnesium valproate, seems to be promising in treating different types of malignant disease, including MDS (Candelaria et al, 2011).…”