Combined molecular modelling and 3D-QSAR study for understanding the inhibition of NQO1 by heterocyclic quinone derivatives

Claudia López-Lira, Jans H. Alzate-Morales, Margot Paulino, Jaime Mella-Raipán, Cristian O. Salas, Ricardo A. Tapia, Jorge Soto-Delgado

Resultado de la investigación: Article

4 Citas (Scopus)

Resumen

A combination of three-dimensional quantitative structure–activity relationship (3D-QSAR), and molecular modelling methods were used to understand the potent inhibitory NAD(P)H:quinone oxidoreductase 1 (NQO1) activity of a set of 52 heterocyclic quinones. Molecular docking results indicated that some favourable interactions of key amino acid residues at the binding site of NQO1 with these quinones would be responsible for an improvement of the NQO1 activity of these compounds. The main interactions involved are hydrogen bond of the amino group of residue Tyr128, π-stacking interactions with Phe106 and Phe178, and electrostatic interactions with flavin adenine dinucleotide (FADH) cofactor. Three models were prepared by 3D-QSAR analysis. The models derived from Model I and Model III, shown leave-one-out cross-validation correlation coefficients (q2 LOO) of.75 and.73 as well as conventional correlation coefficients (R2) of.93 and.95, respectively. In addition, the external predictive abilities of these models were evaluated using a test set, producing the predicted correlation coefficients (r2 pred) of.76 and.74, respectively. The good concordance between the docking results and 3D-QSAR contour maps provides helpful information about a rational modification of new molecules based in quinone scaffold, in order to design more potent NQO1 inhibitors, which would exhibit highly potent antitumor activity.

Idioma originalEnglish
Páginas (desde-hasta)29-38
Número de páginas10
PublicaciónChemical Biology and Drug Design
Volumen91
N.º1
DOI
EstadoPublished - 1 ene 2018

Huella dactilar

Molecular modeling
Quantitative Structure-Activity Relationship
Quinones
Derivatives
Flavin-Adenine Dinucleotide
Static Electricity
NAD
Hydrogen
Oxidoreductases
Binding Sites
Amino Acids
Coulomb interactions
Scaffolds
Hydrogen bonds
benzoquinone
Molecules

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine

Citar esto

López-Lira, Claudia ; Alzate-Morales, Jans H. ; Paulino, Margot ; Mella-Raipán, Jaime ; Salas, Cristian O. ; Tapia, Ricardo A. ; Soto-Delgado, Jorge. / Combined molecular modelling and 3D-QSAR study for understanding the inhibition of NQO1 by heterocyclic quinone derivatives. En: Chemical Biology and Drug Design. 2018 ; Vol. 91, N.º 1. pp. 29-38.
@article{68dc80048ba0475787f5793aa205737d,
title = "Combined molecular modelling and 3D-QSAR study for understanding the inhibition of NQO1 by heterocyclic quinone derivatives",
abstract = "A combination of three-dimensional quantitative structure–activity relationship (3D-QSAR), and molecular modelling methods were used to understand the potent inhibitory NAD(P)H:quinone oxidoreductase 1 (NQO1) activity of a set of 52 heterocyclic quinones. Molecular docking results indicated that some favourable interactions of key amino acid residues at the binding site of NQO1 with these quinones would be responsible for an improvement of the NQO1 activity of these compounds. The main interactions involved are hydrogen bond of the amino group of residue Tyr128, π-stacking interactions with Phe106 and Phe178, and electrostatic interactions with flavin adenine dinucleotide (FADH) cofactor. Three models were prepared by 3D-QSAR analysis. The models derived from Model I and Model III, shown leave-one-out cross-validation correlation coefficients (q2 LOO) of.75 and.73 as well as conventional correlation coefficients (R2) of.93 and.95, respectively. In addition, the external predictive abilities of these models were evaluated using a test set, producing the predicted correlation coefficients (r2 pred) of.76 and.74, respectively. The good concordance between the docking results and 3D-QSAR contour maps provides helpful information about a rational modification of new molecules based in quinone scaffold, in order to design more potent NQO1 inhibitors, which would exhibit highly potent antitumor activity.",
keywords = "3D-QSAR, antitumorals, molecular modelling, NAD(P)H:quinone oxidoreductase 1, naphthoquinones",
author = "Claudia L{\'o}pez-Lira and Alzate-Morales, {Jans H.} and Margot Paulino and Jaime Mella-Raip{\'a}n and Salas, {Cristian O.} and Tapia, {Ricardo A.} and Jorge Soto-Delgado",
year = "2018",
month = "1",
day = "1",
doi = "10.1111/cbdd.13051",
language = "English",
volume = "91",
pages = "29--38",
journal = "Chemical Biology and Drug Design",
issn = "1747-0277",
publisher = "Blackwell",
number = "1",

}

Combined molecular modelling and 3D-QSAR study for understanding the inhibition of NQO1 by heterocyclic quinone derivatives. / López-Lira, Claudia; Alzate-Morales, Jans H.; Paulino, Margot; Mella-Raipán, Jaime; Salas, Cristian O.; Tapia, Ricardo A.; Soto-Delgado, Jorge.

En: Chemical Biology and Drug Design, Vol. 91, N.º 1, 01.01.2018, p. 29-38.

Resultado de la investigación: Article

TY - JOUR

T1 - Combined molecular modelling and 3D-QSAR study for understanding the inhibition of NQO1 by heterocyclic quinone derivatives

AU - López-Lira, Claudia

AU - Alzate-Morales, Jans H.

AU - Paulino, Margot

AU - Mella-Raipán, Jaime

AU - Salas, Cristian O.

AU - Tapia, Ricardo A.

AU - Soto-Delgado, Jorge

PY - 2018/1/1

Y1 - 2018/1/1

N2 - A combination of three-dimensional quantitative structure–activity relationship (3D-QSAR), and molecular modelling methods were used to understand the potent inhibitory NAD(P)H:quinone oxidoreductase 1 (NQO1) activity of a set of 52 heterocyclic quinones. Molecular docking results indicated that some favourable interactions of key amino acid residues at the binding site of NQO1 with these quinones would be responsible for an improvement of the NQO1 activity of these compounds. The main interactions involved are hydrogen bond of the amino group of residue Tyr128, π-stacking interactions with Phe106 and Phe178, and electrostatic interactions with flavin adenine dinucleotide (FADH) cofactor. Three models were prepared by 3D-QSAR analysis. The models derived from Model I and Model III, shown leave-one-out cross-validation correlation coefficients (q2 LOO) of.75 and.73 as well as conventional correlation coefficients (R2) of.93 and.95, respectively. In addition, the external predictive abilities of these models were evaluated using a test set, producing the predicted correlation coefficients (r2 pred) of.76 and.74, respectively. The good concordance between the docking results and 3D-QSAR contour maps provides helpful information about a rational modification of new molecules based in quinone scaffold, in order to design more potent NQO1 inhibitors, which would exhibit highly potent antitumor activity.

AB - A combination of three-dimensional quantitative structure–activity relationship (3D-QSAR), and molecular modelling methods were used to understand the potent inhibitory NAD(P)H:quinone oxidoreductase 1 (NQO1) activity of a set of 52 heterocyclic quinones. Molecular docking results indicated that some favourable interactions of key amino acid residues at the binding site of NQO1 with these quinones would be responsible for an improvement of the NQO1 activity of these compounds. The main interactions involved are hydrogen bond of the amino group of residue Tyr128, π-stacking interactions with Phe106 and Phe178, and electrostatic interactions with flavin adenine dinucleotide (FADH) cofactor. Three models were prepared by 3D-QSAR analysis. The models derived from Model I and Model III, shown leave-one-out cross-validation correlation coefficients (q2 LOO) of.75 and.73 as well as conventional correlation coefficients (R2) of.93 and.95, respectively. In addition, the external predictive abilities of these models were evaluated using a test set, producing the predicted correlation coefficients (r2 pred) of.76 and.74, respectively. The good concordance between the docking results and 3D-QSAR contour maps provides helpful information about a rational modification of new molecules based in quinone scaffold, in order to design more potent NQO1 inhibitors, which would exhibit highly potent antitumor activity.

KW - 3D-QSAR

KW - antitumorals

KW - molecular modelling

KW - NAD(P)H:quinone oxidoreductase 1

KW - naphthoquinones

UR - http://www.scopus.com/inward/record.url?scp=85039074062&partnerID=8YFLogxK

U2 - 10.1111/cbdd.13051

DO - 10.1111/cbdd.13051

M3 - Article

AN - SCOPUS:85039074062

VL - 91

SP - 29

EP - 38

JO - Chemical Biology and Drug Design

JF - Chemical Biology and Drug Design

SN - 1747-0277

IS - 1

ER -