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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. November 2004, Volume 3, Number 11, 704-719 |
Computer-Aided Design of Selective COX-2 Inhibitors: Molecular
Docking of Structurally Diverse Cyclooxygenase-2 Inhibitors using FlexX
Asit K. Chakraborti and Ramasamy Thilagavathi
Internet Electron. J. Mol. Des. 2004, 3, 704-719
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Abstract:
Three-dimensional structures of pharmacologically important
macromolecules offer a route to the discovery of new drugs.
Understanding the macromolecule-ligand interactions and
validation of method used for docking and virtual screening of
chemical databases is crucial step in structure-based design. We
therefore carried out molecular docking for a set of eighty two
structurally diverse COX-1/COX-2 inhibitors including
traditional NSAIDs and the recently developed coxibs using
FlexX method to find out how good this method differentiate
between the active and inactive compounds. FlexX is one of the
fast flexible docking method that uses an incremental
construction algorithm to place ligands into an active site. The
scoring function (empirical binding free energy) of the FlexX
used to estimate the free binding energy of the protein-ligand
complex is called F_score. Reproducibility of the experimental
conformations of the bound ligands such as SC-558,
indomethacin, and flurbiprofen indicates the better performance
of FlexX method. Good correlation between the standard FlexX
score (F_score) and the COX-2 inhibitory activity (pIC50) was
observed. Simple linear regression analysis provided the
correlation coefficient values of 0.731 and 0.670 for two classes
of COX-2 inhibitors. Flexible docking of eighty two structurally
diverse COX-2 inhibitors has been successfully carried out.
Some false positives and false negatives were observed but
considering the limitations of the available docking programs,
the results are encouraging. The in depth analysis of the resulted
COX-2-ligand complexes may improve our knowledge in
understanding the binding interactions in detail. Thus, this study
will be useful for the design of novel COX-2 inhibitors based on
docking and the resulted bioactive conformations of the ligands
will be useful in building structure-based 3-D QSAR model.
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