A docking model of human ribonucleotide reductase with flavin and phenosafranine

Abstract

Ribonucleotide Reductase (RNR) is an enzyme responsible for the reduction of ribonucleotides to their corresponding Deoxyribonucleotides (DNA), which is a building block for DNA replication and repair mechanisms. The key role of RNR in DNA synthesis and control in cell growth has made this an important target for anticancer therapy. Increased RNR activity has been associated with malignant transformation and tumor cell growth. In recent years, several RNR inhibitors, including Triapine, Gemcitabine and GTI-2040, have entered the clinical trials. Our current work focuses on an attempted to dock this inhibitors Flavin and Phenosafranine to curtail the action of human RNR2. The docked inhibitor Flavin and Phenosafranine binds at the active site with THR176, which are essential for free radical formation. The inhibitor must be a radical scavenger to destroy the tyrosyl radical or iron metal scavenger. The iron or radical site of R2 protein can react with one-electron reductants, whereby the tyrosyl radical is converted to a normal tyrosine residue. However, compounds such as Flavin and Phenosafranine were used in most of the cases to reduce the radical activity. The docking study was performed for the crystal structure of human RNR with the radical scavengers Flavin and Phenosafranine to inhibit the human RNR2. This helps to understand the functional aspects and also aids in the development of novel inhibitors for the human RNR2.

Keywords: Flavin; Phenosafranine; Ribonucleotide reductase; inhibitors; radical scavenger.

Figure 1

The Cartoon representation of crystal structure of human RNR R2 subunit which displays the α-helix and the loop region in distinct manner. The structure is rendered using PyMol.

Figure 2

The interaction of Flavin with human RNR was performed using Auto Dock 3.0.5 which displays the residue THR176 interacts with the inhibitor Flavin. THR176 of Human RNR and the inhibitor molecule Flavin were found intact at the end of the docking.

Figure 3

The interaction of phenosafranine with human RNR was performed using Auto Dock 3.0.5 which displays the residue THR176 interacts with the inhibitor phenosafranine. THR176 of Human RNR and the inhibitor molecule phenosafranine were found intact at the end of the docking.