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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. July 2008, Volume 7, Number 7, 142-151 |
Three-Dimensional Molecular Field Analysis of Dihydroindazolocarbazole
Analogues of KDR and Tie-2 Receptor Tyrosine Kinase Inhibitors
Neha Kansal, Om Silakari, and Muttineni Ravikumar
Internet Electron. J. Mol. Des. 2008, 7, 142-151
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Abstract:
Angiogenesis, the formation of new blood vessels from pre-existing vessels has
been considered a critical event for growth and metastasis of solid tumors. KDR
and Tie-2 are two receptor tyrosine kinases (RTK) that play primary role in tumor
angiogenesis. Due to the vital role of RTK signaling in tumor progression,
inhibition of RTK signaling pathways emerged as one of the most compelling
targets for therapeutic intervention in cancer. A set of dihydroindazolocarbazole
analogues reported as RTK inhibitors were analyzed by employing molecular
field analysis (MFA) technique to derive predictive models that may be used to
design of multikinase inhibitors. MFA is one of the 3D-QSAR methods that relate
the biological activity of molecules with steric and electrostatic interactions
between the compound and the probe atom on a rectangular grid according to
Lennard-Jones and Coulomb potentials. MFA studies were performed with the
QSAR module of Cerius2 using genetic partial least squares (G/PLS) algorithm.
MFA was carried out for both KDR and Tie-2 inhibitors and validated using
the leave-one-out cross-validation method. These studies produced reasonably good
predictive models with high cross-validated (0.831 for KDR, 0.957 for Tie-2) and
conventional r2 (0.979 for KDR, 0.978 for Tie-2) values for both the cases. The
QSAR models developed for KDR and Tie-2 inhibitors show good correlation
and predictive ability based on which biological activities for the new molecules
can be predicted. Molecules with dual inhibitory activity against both KDR and
Tie-2 would show synergistic effects by affecting critical stages of blood
vessel formation, and thus potentially leading to a new approach to cancer therapy.
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