|
Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. June 2008, Volume 7, Number 6, 131-141 |
Docking and QSAR Studies for Inhibitors of Thymidylate Synthase
Kotni Meena Kumari, Sivan Sree Kanth, and Manga Vijjulatha
Internet Electron. J. Mol. Des. 2008, 7, 131-141
|
Abstract:
A series of novel antifolate inhibitors having naphthalene core, substituted
quinazoline, indole, pyrrolo-pyrimidine, pyrido-pyrimidine, and pteridine were
designed using computational technique. These molecules were compared with
the known classical and non-classical antifolate inhibitors of the thymidylate
synthase by performing docking studies and by computing their ADME
properties. The designed molecules showed good binding affinity towards the
protein compared to the several thymidylate synthase inhibitors. The biological
activities for these inhibitors were predicted withy a model equation generated by
regression analysis between biological activity (pKi) of known inhibitors and
there E-model which is a specific combination of Glide score, Coulombic and van
der Waals interactions. The MLR QSAR analysis was carried out on 20 analogues
used as training set, and 8 analogues used as test set. This study gave a reasonably
good predictive model with R2 = 0.957
and R2LOO = 0.871 (leave-one-out method).
The cross validation on the test set gave R2cv = 0.587 and RMS = 0.493.
|