JMG-5899; No of Pages 17
Journal of Molecular Graphics and Modelling xxx (2009) xxx–xxx
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Journal of Molecular Graphics and Modelling
journal homepage: www.elsevier.com/locate/JMGM
Genome wide analysis and comparative docking studies of new diaryl furan derivatives against human cyclooxygenase-2, lipoxygenase, thromboxane synthase and prostacyclin synthase enzymes involved in inﬂammatory pathway P. Nataraj Sekhar a, L. Ananda Reddy a,*, Marc De Maeyer b, K. Praveen Kumar c, Y.S. Srinivasulu c, M.S.L. Sunitha a, I.S.N. Sphoorthi d, G. Jayasree d, V. Srikanth e, A. Maruthi Rao f, V.S. Kothekar g, Inder Konka h, P.V.B.S. Narayana i, P.B. Kavi Kishor a a
Department of Genetics, Osmania University, Hyderabad 500 007, India Laboratory of Biomolecular Modelling, Division Biochemistry, Molecular and Structural Biology, Department of Chemistry, Katholieke University, Leuven, Belgium c Srivenkateswara University, Tirupathi 517 501, India d Srinidhi Institute of Science and Technology, Hyderabad 500 007, India e St. Peters Institute of Pharmaceutical Sciences, Warangal 506 001, India f Department of Botany, Telangana University, Nizamabad 503 002, India g Department of Botany, Dr. B.A.M. University, Aurangabad 431 004, India h G. Pullareddy College of Pharmacy, Mehadipatnam, Hyderabad, India i CARISM, SASTRA University, Thanjavur, India b
A R T I C L E I N F O
A B S T R A C T
Article history: Received 20 April 2009 Received in revised form 19 August 2009 Accepted 20 August 2009 Available online xxx Keywords: COX-2 Thromboxane synthase Lipoxygenase Homology modelling Docking
In an effort to develop potent anti-inﬂammatory and antithrombotic drugs, a series of new 4-(2phenyltetrahydrofuran-3-yl) benzene sulfonamide analogs were designed and docked against homology models of human cyclooxygenase-2 (COX-2), lipoxygenase and thromboxane synthase enzymes built using MODELLER 7v7 software and reﬁned by molecular dynamics for 2 ns in a solvated layer. Validation of these homology models by procheck, verify-3D and ERRAT programs revealed that these models are highly reliable. Docking studies of 4-(2-phenyltetrahydrofuran-3-yl) benzene sulfonamide analogs designed by substituting different chemical groups on benzene rings replacing 1H pyrazole in celecoxib with ﬁve membered thiophene, furan, 1H pyrrole, 1H imidazole, thiazole and 1,3-oxazole showed that diaryl furan molecules showed good binding afﬁnity towards mouse COX-2. Further, docking studies of diaryl furan derivatives are likely to have superior thromboxane synthase and COX-2 selectivity. Docking studies against site directed mutagenesis of Arg120Ala, Ser530Ala, Ser530Met and Tyr355Phe enzymes displayed the effect of inhibition of COX-2. Drug likeliness and activity decay for these inhibitors showed that these molecules act as best drugs at very low concentrations. ß 2009 Elsevier Inc. All rights reserved.
1. Introduction Cyclooxygenase-2 (COX-2) is an important enzyme responsible for the formation of biological mediators called prostanoids  including prostaglandins (PGs), prostacyclins and thromboxanes . PGs are ubiquitous fatty-acid derivatives that serve as autocrine/paracrine mediators involved in many different physiological processes. Non-steroidal antiinﬂamatory drugs and COX-2 inhibitors bind to COX-2 and provide relief from the symptoms of pain and inﬂammation. COX converts arachidonic acid (AA, a v-6 essential fatty acid) to prostaglandin H2 (PGH2), the precursor of the series-2 prostanoids . The resulting PGH2 acts as a substrate
* Corresponding author. Tel.: +91 40 2768 2335; fax: +91 40 2709 5178. E-mail address: email@example.com (L.A. Reddy). 1093-3263/$ – see front matter ß 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.jmgm.2009.08.010
for isomerase pathways that produce other PG, thromboxane, and prostacyclin isomers. The enzyme contains two active...