A 3D QSAR pharmacophore model and quantum chemical structure-activity analysis of chloroquine(CQ)-resistance reversal

Apurba K. Bhattacharjee, Dennis E. Kyle, Jonathan L. Vennerstrom, Wilbur K. Milhous

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Using CATALYST, a three-dimensional QSAR pharmacophore model for chloroquine(CQ)-resistance reversal was developed from a training set of 17 compounds. These included imipramine (1), desipramine (2), and 15 of their analogues (3-17), some of which fully reversed CQ-resistance, while others were without effect. The generated pharmacophore model indicates that two aromatic hydrophobic interaction sites on the tricyclic ring and a hydrogen bond acceptor (lipid) site at the side chain, preferably on a nitrogen atom, are necessary for potent activity. Stereoelectronic properties calculated by using AM1 semiempirical calculations were consistent with the model, particularly the electrostatic potential profiles characterized by a localized negative potential region by the side chain nitrogen atom and a large region covering the aromatic ring. The calculated data further revealed that aminoalkyl substitution at the N5-position of the heterocycle and a secondary or tertiary aliphatic aminoalkyl nitrogen atom with a two or three carbon bridge to the heteroaromatic nitrogen (N5) are required for potent "resistance reversal activity". Lowest energy conformers for 1-17 were determined and optimized to afford stereoelectronic properties such as molecular orbital energies, electrostatic potentials, atomic charges, proton affinities, octanol-water partition coefficients (log P), and structural parameters. For 1-17, fairly good correlation exists between resistance reversal activity and intrinsic basicity of the nitrogen atom at the tricyclic ring system, frontier orbital energies, and lipophilicity. Significantly, nine out of 11 of a group of structurally diverse CQ-resistance reversal agents mapped very well on the 3D QSAR pharmacophore model.

Original languageEnglish (US)
Pages (from-to)1212-1220
Number of pages9
JournalJournal of Chemical Information and Computer Sciences
Volume42
Issue number5
DOIs
StatePublished - Sep 1 2002

Fingerprint

activity structure
Chloroquine
Nitrogen
Atoms
energy
Electrostatics
Octanols
Desipramine
Imipramine
Molecular orbitals
Alkalinity
substitution
Lipids
Protons
Hydrogen bonds
Substitution reactions
Carbon
water
Water
interaction

ASJC Scopus subject areas

  • Chemistry(all)
  • Information Systems
  • Computer Science Applications
  • Computational Theory and Mathematics

Cite this

A 3D QSAR pharmacophore model and quantum chemical structure-activity analysis of chloroquine(CQ)-resistance reversal. / Bhattacharjee, Apurba K.; Kyle, Dennis E.; Vennerstrom, Jonathan L.; Milhous, Wilbur K.

In: Journal of Chemical Information and Computer Sciences, Vol. 42, No. 5, 01.09.2002, p. 1212-1220.

Research output: Contribution to journalArticle

@article{d7c77f42f9b041d5b3a7b5c393128da6,
title = "A 3D QSAR pharmacophore model and quantum chemical structure-activity analysis of chloroquine(CQ)-resistance reversal",
abstract = "Using CATALYST, a three-dimensional QSAR pharmacophore model for chloroquine(CQ)-resistance reversal was developed from a training set of 17 compounds. These included imipramine (1), desipramine (2), and 15 of their analogues (3-17), some of which fully reversed CQ-resistance, while others were without effect. The generated pharmacophore model indicates that two aromatic hydrophobic interaction sites on the tricyclic ring and a hydrogen bond acceptor (lipid) site at the side chain, preferably on a nitrogen atom, are necessary for potent activity. Stereoelectronic properties calculated by using AM1 semiempirical calculations were consistent with the model, particularly the electrostatic potential profiles characterized by a localized negative potential region by the side chain nitrogen atom and a large region covering the aromatic ring. The calculated data further revealed that aminoalkyl substitution at the N5-position of the heterocycle and a secondary or tertiary aliphatic aminoalkyl nitrogen atom with a two or three carbon bridge to the heteroaromatic nitrogen (N5) are required for potent {"}resistance reversal activity{"}. Lowest energy conformers for 1-17 were determined and optimized to afford stereoelectronic properties such as molecular orbital energies, electrostatic potentials, atomic charges, proton affinities, octanol-water partition coefficients (log P), and structural parameters. For 1-17, fairly good correlation exists between resistance reversal activity and intrinsic basicity of the nitrogen atom at the tricyclic ring system, frontier orbital energies, and lipophilicity. Significantly, nine out of 11 of a group of structurally diverse CQ-resistance reversal agents mapped very well on the 3D QSAR pharmacophore model.",
author = "Bhattacharjee, {Apurba K.} and Kyle, {Dennis E.} and Vennerstrom, {Jonathan L.} and Milhous, {Wilbur K.}",
year = "2002",
month = "9",
day = "1",
doi = "10.1021/ci0200265",
language = "English (US)",
volume = "42",
pages = "1212--1220",
journal = "Journal of Chemical Information and Modeling",
issn = "1549-9596",
publisher = "American Chemical Society",
number = "5",

}

TY - JOUR

T1 - A 3D QSAR pharmacophore model and quantum chemical structure-activity analysis of chloroquine(CQ)-resistance reversal

AU - Bhattacharjee, Apurba K.

AU - Kyle, Dennis E.

AU - Vennerstrom, Jonathan L.

AU - Milhous, Wilbur K.

PY - 2002/9/1

Y1 - 2002/9/1

N2 - Using CATALYST, a three-dimensional QSAR pharmacophore model for chloroquine(CQ)-resistance reversal was developed from a training set of 17 compounds. These included imipramine (1), desipramine (2), and 15 of their analogues (3-17), some of which fully reversed CQ-resistance, while others were without effect. The generated pharmacophore model indicates that two aromatic hydrophobic interaction sites on the tricyclic ring and a hydrogen bond acceptor (lipid) site at the side chain, preferably on a nitrogen atom, are necessary for potent activity. Stereoelectronic properties calculated by using AM1 semiempirical calculations were consistent with the model, particularly the electrostatic potential profiles characterized by a localized negative potential region by the side chain nitrogen atom and a large region covering the aromatic ring. The calculated data further revealed that aminoalkyl substitution at the N5-position of the heterocycle and a secondary or tertiary aliphatic aminoalkyl nitrogen atom with a two or three carbon bridge to the heteroaromatic nitrogen (N5) are required for potent "resistance reversal activity". Lowest energy conformers for 1-17 were determined and optimized to afford stereoelectronic properties such as molecular orbital energies, electrostatic potentials, atomic charges, proton affinities, octanol-water partition coefficients (log P), and structural parameters. For 1-17, fairly good correlation exists between resistance reversal activity and intrinsic basicity of the nitrogen atom at the tricyclic ring system, frontier orbital energies, and lipophilicity. Significantly, nine out of 11 of a group of structurally diverse CQ-resistance reversal agents mapped very well on the 3D QSAR pharmacophore model.

AB - Using CATALYST, a three-dimensional QSAR pharmacophore model for chloroquine(CQ)-resistance reversal was developed from a training set of 17 compounds. These included imipramine (1), desipramine (2), and 15 of their analogues (3-17), some of which fully reversed CQ-resistance, while others were without effect. The generated pharmacophore model indicates that two aromatic hydrophobic interaction sites on the tricyclic ring and a hydrogen bond acceptor (lipid) site at the side chain, preferably on a nitrogen atom, are necessary for potent activity. Stereoelectronic properties calculated by using AM1 semiempirical calculations were consistent with the model, particularly the electrostatic potential profiles characterized by a localized negative potential region by the side chain nitrogen atom and a large region covering the aromatic ring. The calculated data further revealed that aminoalkyl substitution at the N5-position of the heterocycle and a secondary or tertiary aliphatic aminoalkyl nitrogen atom with a two or three carbon bridge to the heteroaromatic nitrogen (N5) are required for potent "resistance reversal activity". Lowest energy conformers for 1-17 were determined and optimized to afford stereoelectronic properties such as molecular orbital energies, electrostatic potentials, atomic charges, proton affinities, octanol-water partition coefficients (log P), and structural parameters. For 1-17, fairly good correlation exists between resistance reversal activity and intrinsic basicity of the nitrogen atom at the tricyclic ring system, frontier orbital energies, and lipophilicity. Significantly, nine out of 11 of a group of structurally diverse CQ-resistance reversal agents mapped very well on the 3D QSAR pharmacophore model.

UR - http://www.scopus.com/inward/record.url?scp=0036708526&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0036708526&partnerID=8YFLogxK

U2 - 10.1021/ci0200265

DO - 10.1021/ci0200265

M3 - Article

C2 - 12377011

AN - SCOPUS:0036708526

VL - 42

SP - 1212

EP - 1220

JO - Journal of Chemical Information and Modeling

JF - Journal of Chemical Information and Modeling

SN - 1549-9596

IS - 5

ER -