A combination of 3D-QSAR, docking, local-binding energy (LBE) and GRID study of the species differences in the carcinogenicity of benzene derivatives chemicals

Filip Fratev, Emilio Benfenati

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

A combination of 3D-QSAR, docking, local-binding energy (LBE) and GRID methods was applied as a tool to study and predict the mechanism of action of 100 carcinogenic benzene derivatives. Two 3D-QSAR models were obtained: (i) model of mouse carcinogenicity on the basis of 100 chemicals (model 1) and (ii) model of the differences in mouse and rat carcinogenicity on the basis of 73 compounds (model 2). 3D-QSAR regression maps indicated the important differences in species carcinogenicity, and the molecular positions associated with them. In order to evaluate the role of P450 metabolic process in carcinogenicity, the following approaches were used. The 3D models of CYP2E1 for mouse and rat were built up. A docking study was applied and the important ligand-protein residues interactions and oxidation positions of the molecules were identified. A new approach for quantitative assessment of metabolism pathways was developed, which enabled us to describe the species differences in CYP2E1 metabolism, and how it can be related to differences in the carcinogenic potential for a subset of compounds. The binding energies of the important substituents (local-binding energy-LBE) were calculated, in order to quantitatively demonstrate the contribution of the substituents in metabolic processes. Furthermore, a computational procedure was used for determining energetically favourable binding sites (GRID examination) of the enzymes. The GRID procedure allowed the identification of some important differences, related to species metabolism in CYP2E1. Comparing GRID, 3D-QSAR maps and LBE results, a similarity was identified, indicating a relationship between P450 metabolic processes and the differences in the carcinogenicity.

Original languageEnglish
Pages (from-to)147-160
Number of pages14
JournalJournal of Molecular Graphics and Modelling
Volume27
Issue number2
DOIs
Publication statusPublished - Sep 2008

Fingerprint

Benzene Derivatives
Binding energy
Benzene
binding energy
benzene
Derivatives
Cytochrome P-450 CYP2E1
metabolism
Metabolism
mice
rats
Rats
Binding sites
set theory
enzymes
regression analysis
Enzymes
examination
Binding Sites
Ligands

Keywords

  • 3D-QSAR
  • Carcinogenicity
  • Docking
  • GRID
  • LBE
  • P450

ASJC Scopus subject areas

  • Physical and Theoretical Chemistry
  • Spectroscopy
  • Atomic and Molecular Physics, and Optics

Cite this

@article{3380f140bd884bd3b966da1c5111b819,
title = "A combination of 3D-QSAR, docking, local-binding energy (LBE) and GRID study of the species differences in the carcinogenicity of benzene derivatives chemicals",
abstract = "A combination of 3D-QSAR, docking, local-binding energy (LBE) and GRID methods was applied as a tool to study and predict the mechanism of action of 100 carcinogenic benzene derivatives. Two 3D-QSAR models were obtained: (i) model of mouse carcinogenicity on the basis of 100 chemicals (model 1) and (ii) model of the differences in mouse and rat carcinogenicity on the basis of 73 compounds (model 2). 3D-QSAR regression maps indicated the important differences in species carcinogenicity, and the molecular positions associated with them. In order to evaluate the role of P450 metabolic process in carcinogenicity, the following approaches were used. The 3D models of CYP2E1 for mouse and rat were built up. A docking study was applied and the important ligand-protein residues interactions and oxidation positions of the molecules were identified. A new approach for quantitative assessment of metabolism pathways was developed, which enabled us to describe the species differences in CYP2E1 metabolism, and how it can be related to differences in the carcinogenic potential for a subset of compounds. The binding energies of the important substituents (local-binding energy-LBE) were calculated, in order to quantitatively demonstrate the contribution of the substituents in metabolic processes. Furthermore, a computational procedure was used for determining energetically favourable binding sites (GRID examination) of the enzymes. The GRID procedure allowed the identification of some important differences, related to species metabolism in CYP2E1. Comparing GRID, 3D-QSAR maps and LBE results, a similarity was identified, indicating a relationship between P450 metabolic processes and the differences in the carcinogenicity.",
keywords = "3D-QSAR, Carcinogenicity, Docking, GRID, LBE, P450",
author = "Filip Fratev and Emilio Benfenati",
year = "2008",
month = "9",
doi = "10.1016/j.jmgm.2008.04.004",
language = "English",
volume = "27",
pages = "147--160",
journal = "Journal of Molecular Graphics and Modelling",
issn = "1093-3263",
publisher = "Elsevier Inc.",
number = "2",

}

TY - JOUR

T1 - A combination of 3D-QSAR, docking, local-binding energy (LBE) and GRID study of the species differences in the carcinogenicity of benzene derivatives chemicals

AU - Fratev, Filip

AU - Benfenati, Emilio

PY - 2008/9

Y1 - 2008/9

N2 - A combination of 3D-QSAR, docking, local-binding energy (LBE) and GRID methods was applied as a tool to study and predict the mechanism of action of 100 carcinogenic benzene derivatives. Two 3D-QSAR models were obtained: (i) model of mouse carcinogenicity on the basis of 100 chemicals (model 1) and (ii) model of the differences in mouse and rat carcinogenicity on the basis of 73 compounds (model 2). 3D-QSAR regression maps indicated the important differences in species carcinogenicity, and the molecular positions associated with them. In order to evaluate the role of P450 metabolic process in carcinogenicity, the following approaches were used. The 3D models of CYP2E1 for mouse and rat were built up. A docking study was applied and the important ligand-protein residues interactions and oxidation positions of the molecules were identified. A new approach for quantitative assessment of metabolism pathways was developed, which enabled us to describe the species differences in CYP2E1 metabolism, and how it can be related to differences in the carcinogenic potential for a subset of compounds. The binding energies of the important substituents (local-binding energy-LBE) were calculated, in order to quantitatively demonstrate the contribution of the substituents in metabolic processes. Furthermore, a computational procedure was used for determining energetically favourable binding sites (GRID examination) of the enzymes. The GRID procedure allowed the identification of some important differences, related to species metabolism in CYP2E1. Comparing GRID, 3D-QSAR maps and LBE results, a similarity was identified, indicating a relationship between P450 metabolic processes and the differences in the carcinogenicity.

AB - A combination of 3D-QSAR, docking, local-binding energy (LBE) and GRID methods was applied as a tool to study and predict the mechanism of action of 100 carcinogenic benzene derivatives. Two 3D-QSAR models were obtained: (i) model of mouse carcinogenicity on the basis of 100 chemicals (model 1) and (ii) model of the differences in mouse and rat carcinogenicity on the basis of 73 compounds (model 2). 3D-QSAR regression maps indicated the important differences in species carcinogenicity, and the molecular positions associated with them. In order to evaluate the role of P450 metabolic process in carcinogenicity, the following approaches were used. The 3D models of CYP2E1 for mouse and rat were built up. A docking study was applied and the important ligand-protein residues interactions and oxidation positions of the molecules were identified. A new approach for quantitative assessment of metabolism pathways was developed, which enabled us to describe the species differences in CYP2E1 metabolism, and how it can be related to differences in the carcinogenic potential for a subset of compounds. The binding energies of the important substituents (local-binding energy-LBE) were calculated, in order to quantitatively demonstrate the contribution of the substituents in metabolic processes. Furthermore, a computational procedure was used for determining energetically favourable binding sites (GRID examination) of the enzymes. The GRID procedure allowed the identification of some important differences, related to species metabolism in CYP2E1. Comparing GRID, 3D-QSAR maps and LBE results, a similarity was identified, indicating a relationship between P450 metabolic processes and the differences in the carcinogenicity.

KW - 3D-QSAR

KW - Carcinogenicity

KW - Docking

KW - GRID

KW - LBE

KW - P450

UR - http://www.scopus.com/inward/record.url?scp=52049085030&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=52049085030&partnerID=8YFLogxK

U2 - 10.1016/j.jmgm.2008.04.004

DO - 10.1016/j.jmgm.2008.04.004

M3 - Article

C2 - 18495507

AN - SCOPUS:52049085030

VL - 27

SP - 147

EP - 160

JO - Journal of Molecular Graphics and Modelling

JF - Journal of Molecular Graphics and Modelling

SN - 1093-3263

IS - 2

ER -