In the present work, modelling study has been performed to explore the physicochemical requirements of 2-sulfonyl-phenyl-3-phenyl-indole analogs as COX-2 enzyme inhibitors. The multivariant regression expressions were developed using sequential multiple linear regression (SEQ-MLR) technique, considering adjustable correlation coefficient (r(adj)(2)). The statistical quality of SEQ-MLR equations was evaluated considering parameters like correlation coefficient (r), standard error of estimation (SEE), and variance ratio (F) at explicit degree of freedom (df). Orthogonality of the descriptors in SEQ-MLR was established through variance inflation factor (VIF). Developed equations have been internally validated using leave-one-out technique and further validated with test set, considering predictive squared correlation coefficient (r(pred)(2)). The orientation of the most potent and selective COX-2 inhibitor of training set, 2-(4-phenyl sulfonamide)-3-phenyl-5-methylindole, in the COX-2 active site was explored by docking. The phenyl sulfonamide moiety positioned in secondary pocket of enzyme which consists of amino acid residues Phe(518), Gln(192), Arg(513), Leu(352), Ser(353) and Val(523) is responsible for the selectivity. The unsubstituted phenyl ring positions in a hydrophobic cavity are lined by Tyr(385), Trp(387), Tyr(348), Leu(384) and Met(522). Interestingly, the indole C-5 CH(3)-substituent is located in a hydrophobic region formed by Ile(345), Val(349), Ala(527), Leu(531) and Leu(534). The hydrophobic interactions of methyl group might be crucial for the potency of 2-sulfonyl-phenyl-3-phenyl-indole analogs. Study has revealed that atomic van der Waals volume and atomic masses explain COX-2 inhibitory activity of 2-sulfonyl-phenyl-3-phenyl-indole analogs significantly.