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Pharmacophore generation and atom-based 3D-QSAR of novel 2-(4-methylsulfonylphenyl)pyrimidines as COX-2 inhibitors

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Abstract

Cyclooxygenase-2 (COX-2) inhibitors are widely used for the treatment of pain and inflammatory disorders such as rheumatoid arthritis and osteoarthritis. A series of novel 2-(4-methylsulfonylphenyl)pyrimidine derivatives has been reported as COX-2 inhibitors. In order to understand the structural requirement of these COX-2 inhibitors, a ligand-based pharmacophore and atom-based 3D-QSAR model have been developed. A five-point pharmacophore with four hydrogen bond acceptors (A) and one hydrogen bond donor (D) was obtained. The pharmacophore hypothesis yielded a 3D-QSAR model with good partial least-square (PLS) statistics results. The training set correlation is characterized by PLS factors (r 2 = 0.642, SD = 0.65, F = 82.7, P = 7.617 e − 12). The test set correlation is characterized by PLS factors (Q 2 ext = 0.841, RMSE = 0.24,Pearson−R = 0.91). A docking study revealed the binding orientations of these inhibitors at active site amino acid residues (Arg513, Val523, Phe518, Ser530, Tyr355, His90) of COX-2 enzyme. The results of ligand-based pharmacophore hypothesis and atom-based 3D-QSAR give detailed structural insights as well as highlights important binding features of novel 2-(4-methylsulfonylphenyl)pyrimidine derivatives as COX-2 inhibitors which can provide guidance for the rational design of novel potent COX-2 inhibitors.

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Authors and Affiliations

  1. Department of Pharmaceutical Chemistry, Poona College of Pharmacy, Bharati Vidyapeeth University, Erandwane, Pune, 411038, India

    Ujashkumar A. Shah, Hemantkumar S. Deokar, Shivajirao S. Kadam & Vithal M. Kulkarni

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  1. Ujashkumar A. Shah
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  2. Hemantkumar S. Deokar
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  3. Shivajirao S. Kadam
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  4. Vithal M. Kulkarni
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Correspondence to Vithal M. Kulkarni.

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Shah, U.A., Deokar, H.S., Kadam, S.S. et al. Pharmacophore generation and atom-based 3D-QSAR of novel 2-(4-methylsulfonylphenyl)pyrimidines as COX-2 inhibitors. Mol Divers 14, 559–568 (2010). https://doi.org/10.1007/s11030-009-9183-3

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