Atom-based QSAR and 3D QSAR using pharmacophore based alignment for discovery of nimesulide-derived SKBR-3 cell line inhibitors

Abstract

Growth suppression of many non-COX-2 expressing tumor cells can be exhibited by COX-2 inhibitors, where supplementation of cells with exogenous prostaglandins fails to rescue the cells from growth inhibition. It can, therefore, be speculated that anti-cancer properties of some COX-2 inhibitors may be contributed by the COX-2-independent effects also. Some of the derivatives obtained from certain COX-2 inhibitors which show non-COX-2 inhibitory mechanism have revealed some significant anti-cancer activities. From a COX-2 selective inhibitor nimesulide, an analog JCC76 is derived which is a non-COX-2 active compound and shows inhibition of SKBR-3 breast cancer cell growth. Other JCC76 derived inhibitors also played significant role in SKBR-3 cell inhibition. An analog-based study was done using pharmacophore modeling and 3D-QSAR to provide clues for potential lead compound designing. A five point pharmacophore ADHRR was generated using 39 JCC76-derived SKBR-3 inhibitors. The validated pharmacophore alignment was used for further 3D-QSAR analysis, which presented a good R 2 value of 0.562, 0.982, and 0.848 for atombased QSAR, CoMFA, and CoMSIA model, respectively. All the QSAR models presented good statistical significance and predictivity. The corresponding Q 2 values for each model are 0.513, 0.649, and 0.518, respectively. Both the pharmacophore and CoMSIA results displayed that the H-bond donor and acceptor sites are the key structural feature for JCC76-derived non-COX-2-dependent inhibitors with high activity.