Importance of Alignment in Developing 3-D QSAR Models of 1,5-Diaryl Pyrazoles for the Prediction of COX-2 Inhibitory Activity #
BioChem Press, Ramasamy Thilagavathi, Asit K. Chakraborti · 2005
Motivation. 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. Method. 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. Results. 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 (r 2 cv