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.
Highlights
Ribonucleotide Reductase (RNR) is a ubiquitous cytosolic enzyme in the cell, responsible for converting ribonucleotides into deoxyribonucleotides, the eventual substrates for DNA polymerase [13], and repair DNA in all living cells [4]
Receptor and ligand data: Radical scavengers from R2 protein are very essential for inhibiting the RNR activity and DNA replication
Based on brief Literature survey [4, 9], the potential radical scavengers Flavin and Phenosafranine molecules are constructed using Insight [10] and subsequently these small molecules were subjected to energy minimization to bring the energy level of the system to global minima, structurally stable and free from steric clashes
Summary
Ribonucleotide Reductase (RNR) is a ubiquitous cytosolic enzyme in the cell, responsible for converting ribonucleotides into deoxyribonucleotides, the eventual substrates for DNA polymerase [13], and repair DNA in all living cells [4] In mammalian cells, this enzyme contains two dissimilar protein components, R1 and R2, which are encoded by two different genes located on different chromosomes [5]. Ribonucleotide reductase (RR) is the rate- limiting enzyme of de novo DNA synthesis and has been shown to be up regulated linked with proliferation and malignant transformation. It was identified as an excellent target for ant tumor therapy [7]. It is said earliar that Ribonucleotide reductase (RNR) activity is necessary for DNA replication and inhibition of this enzyme will inhibits cell division.
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