Molecular dynamics simulation studies for DNA sequence recognition by reactive metabolites of anticancer compounds

Abstract

The discovery of novel anticancer molecules 5F-203 (NSC703786) and 5-aminoflavone (5-AMF, NSC686288) has addressed the issues of toxicity and reduced efficacy by targeting over expressed Cytochrome P450 1A1 (CYP1A1) in cancer cells. CYP1A1 metabolizes these compounds into their reactive metabolites, which are proven to mediate their anticancer effect through DNA adduct formation. However, the drug metabolite-DNA binding has not been explored so far. Hence, understanding the binding characteristics and molecular recognition for drug metabolites with DNA is of practical and fundamental interest. The present study is aimed to model binding preference shown by reactive metabolites of 5F-203 and 5-AMF with DNA in forming DNA adducts. To perform this, three different DNA crystal structures covering sequence diversity were selected, and 12 DNA-reactive metabolite complexes were generated. Molecular dynamics simulations for all complexes were performed using AMBER 11 software after development of protocol for DNA-reactive metabolite system. Furthermore, the MM-PBSA/GBSA energy calculation, per-nucleotide energy decomposition, and Molecular Electrostatic Surface Potential analysis were performed. The results obtained from present study clearly indicate that minor groove in DNA is preferable for binding of reactive metabolites of anticancer compounds. The binding preferences shown by reactive metabolites were also governed by specific nucleotide sequence and distribution of electrostatic charges in major and minor groove of DNA structure. Overall, our study provides useful insights into the initial step of mechanism of reactive metabolite binding to the DNA and the guidelines for designing of sequence specific DNA interacting anticancer agents.

The aryl hydrocarbon receptor (AhR) as a breast cancer drug target

“…The metabolic profile of AF demonstrated that CYP1A1 and sulfotransferase 1A1 (SULT1A1) metabolize the two amino groups successively, initially to toxic hydroxylamines, then to active nitrenium ions (Scheme ) . Nitrenium ion species bind with DNA, forming DNA adducts; leading to cell death . The di‐nitrenium ion 26 inhibits DNA synthesis via inducement of S‐phase arrest and replication‐dependent histone H2AX phosphorylation; resulting in DNA double‐strand breaks and ultimately cytotoxicity .…”

Characterization of differences in substrate specificity among CYP1A1, CYP1A2 and CYP1B1: an integrated approach employing molecular docking and molecular dynamics simulations

“…Elucidation of substrate specificity between CYP1A1, CYP1A2 and CYP1B1 has been a matter of concern, which is evident from the numerous studies conducted in this regard Nandekar et al, 2013;Pragyan et al, 2014;Tumbi et al, 2014). Recently, the comparative protein structure analysis of the three isoforms of CYP1 family of enzymes was published that focused on sequence alignment (sequence differences), root mean square deviation (RMSD) analysis and B-factor analysis to give a better understanding of the macromolecular features involved in substrate specificity and to understand the interplay between protein dynamics and functions, which have important implications on rational design of anticancer drugs .…”

Recent Developments and Applications of the MMPBSA Method

“…Basic mechanistic studies were carried out, including cationic porphyrin-anthraquinone hybrids binding to DNA duplexes (Arba and Tjahjono, 2015 ) and G-quadruplexes (Arba et al, 2016 ), as well as ligands binding to riboswitches upon mutation (Hu et al, 2017 ). The interactions of reactive metabolites of anticancer compounds with DNA were also analyzed (Tumbi et al, 2014 ). In the binding of ligands to riboswitches, Hu et al analyzed the relative binding free energies for a guanine riboswitch (GR) and a GUA complex relative to three complexes: 6GU (3.4 kcal/mol), 2BP (5.48 kcal/mol), and XAN (6.19 kcal/mol).…”