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Internet Electronic Journal of Molecular Design - IEJMD, ISSN 1538-6414, CODEN IEJMAT
| ABSTRACT - Internet Electron. J. Mol. Des. September 2005, Volume 4, Number 9, 603-612 |
Importance of Alignment in Developing 3-D QSAR Models of 1,5-Diaryl Pyrazoles
for the Prediction of COX-2 Inhibitory Activity
Ramasamy Thilagavathi and Asit K. Chakraborti
Internet Electron. J. Mol. Des. 2005, 4, 603-612
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Abstract:
A set of thirty-four 1,5-diaryl pyrazoles having selective COX-2
inhibitory activity were analyzed using Comparative Molecular
Field Analysis (CoMFA) and Comparative Molecular Similarity
Indices Analysis (CoMSIA). One of the important steps in
CoMFA is the derivation of active conformation and alignment
of molecules. The success of CoMFA depends on the relative
positioning of the ligands in the fixed lattice, prior to generation
of the 3-D descriptors. Thus, we performed two different
alignments such as as_is database alignment (the as_is option in
the database alignment is used to align molecules to the template
without changing the orientation) and the alignment based on
FlexX docking. The first method is based solely on the selection
of ligand atoms and the second method involves protein based
docking and use of the docked conformations. CoMFA is one of
the popular 3-D QSAR methods that relate the biological activity
of a series of molecules with steric and electrostatic fields
sampled at grid points defining a large 3-D box around the
molecule. CoMSIA is a recently introduced 3-D QSAR method
that includes additional parameters such as hydrophobicity,
hydrogen bond donor and hydrogen bond acceptor properties
along with steric and electrostatic fields. FlexX is one of the fast
flexible docking methods that uses an incremental construction
algorithm to place ligands into an active site. The scoring
function (empirical binding free energy) of the FlexX is used to
estimate the free binding energy of the protein-ligand complex.
Compared to the alignment method involving the docked
conformations, the atom-based alignment produced better
CoMFA and CoMSIA results. Under the atom-based alignment,
CoMFA produced a model (r2cv = 0.693,
r2conv = 0.989, SEE = 0.196)
better than that of CoMSIA (r2cv = 0.370,
r2conv = 0.914,
SEE = 0.519). The contour maps produced by CoMFA model
could rationalize the COX-2 inhibitory activity profile of many
compounds used in the present study. The importance of
alignment of molecules in deriving the 3-D QSAR model was
revealed from a comparative study of atom-based alignment and
alignment method involving the docked conformations. The
resulted contour maps from CoMFA could be used to understand
the important structural features responsible for COX-2
inhibitory activities of 1,5-diaryl pyrazoles.
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