Computer-aided design of non sulphonyl COX-2 inhibitors: an improved comparative molecular field analysis incorporating additional descriptors and comparative molecular similarity indices analysis of 1,3-diarylisoindole derivatives.

A set of thirty five molecules of 1,3-diaryl-4,5,6,7-tetrahydro-2H-isoindoles endowed with selective COX-2 inhibitory activity was analyzed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA). Besides conventional steric and electrostatic fields, seven additional descriptors were incorporated to the CoMFA models. An improved CoMFA model (r(2)(cv)=0.536, r(2)(conv)=0.968, SEE=0.222, r(2)(pred)=0.6564) was obtained by taking into account the CMR as additional descriptor. This analysis provided useful information regarding the pharmacophoric requirements for COX-2 inhibitory activity. FlexX was used to find out the binding orientation of this new class of 1,3-diaryl isoindoles in the active site of COX-2. The contour maps produced by improved CoMFA model was superimposed onto the active site revealing a good correlation between the contour maps and the active site residue interactions.