Development of a chirality-sensitive flexibility descriptor for 3+3D-QSAR

Máté Dervarics, F. Ötvös, T. Martinek

Research output: Article

20 Citations (Scopus)

Abstract

Multidimensional QSAR methodologies can be used to predict the active conformation encoded in the conformational preferences of molecules in an active series by utilizing conformational sampling. In the 3+3D-QSAR approach, the conformational free energy loss is modeled with internal coordinate-based flexibility descriptors. While the pharmacophore point pair distance descriptors introduced earlier proved useful in the construction of QSAR models and in the prediction of important features of the active conformation, they are inherently incapable of describing the chiral arrangement of the pharmacophores. As an improvement, a chirality-sensitive flexibility (CSF) descriptor is now introduced, which is based on the distance between a pharmacophore point and a plane defined by three pharmacophore points. The performance of the CSF descriptor was tested on two active series: 37 endomorphin analogues with opiate activity and 38 PGF2α analogues with antinidatory activity. The newly devised descriptor resulted in improved QSAR models in terms of both prediction accuracy and precision of the chiral geometric features of the predicted active conformations.

Original languageEnglish
Pages (from-to)1431-1438
Number of pages8
JournalJournal of Chemical Information and Modeling
Volume46
Issue number3
DOIs
Publication statusPublished - máj. 2006

Fingerprint

Chirality
Conformations
flexibility
Opiate Alkaloids
Dinoprost
Free energy
Energy dissipation
Sampling
energy
Molecules
methodology
performance

ASJC Scopus subject areas

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

Cite this

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abstract = "Multidimensional QSAR methodologies can be used to predict the active conformation encoded in the conformational preferences of molecules in an active series by utilizing conformational sampling. In the 3+3D-QSAR approach, the conformational free energy loss is modeled with internal coordinate-based flexibility descriptors. While the pharmacophore point pair distance descriptors introduced earlier proved useful in the construction of QSAR models and in the prediction of important features of the active conformation, they are inherently incapable of describing the chiral arrangement of the pharmacophores. As an improvement, a chirality-sensitive flexibility (CSF) descriptor is now introduced, which is based on the distance between a pharmacophore point and a plane defined by three pharmacophore points. The performance of the CSF descriptor was tested on two active series: 37 endomorphin analogues with opiate activity and 38 PGF2α analogues with antinidatory activity. The newly devised descriptor resulted in improved QSAR models in terms of both prediction accuracy and precision of the chiral geometric features of the predicted active conformations.",
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