Computer simulation of the in vitro and in vivo anti-inflammatory activities of dihydropyrimidines acid derivatives thro
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Med Chem Res (2013) 22:2493–2504 DOI 10.1007/s00044-012-0244-2
ORIGINAL RESEARCH
Computer simulation of the in vitro and in vivo anti-inflammatory activities of dihydropyrimidines acid derivatives through the inhibition of cyclooxygenase-2 Raksha Dhankar • Anjali M. Rahatgaonkar Rakesh Shukla • Mukund Chorghade • Ashutosh Tiwari
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Received: 7 May 2012 / Accepted: 14 September 2012 / Published online: 27 September 2012 Ó Springer Science+Business Media New York 2012
Abstract Simulation of virtually designed 20 compounds as COX-2 inhibitors using molecular modelling of protein– ligand interactions to predict drug structure–activity relationship was performed in this study. A synthetic route with a rational chemical approach to (E)-2-oxo-(thio)-4-substituted phenyl-6-styryl-1,2,3,4-tetrahydro-pyrimidine-5-caboxylic acid was designed and demonstrated. A comparative analysis of antimetabolite drug and corresponding metabolites (virtually designed compounds) provided a better understanding of rational drug design. COX-1(pdb entry: 1eqg) and COX-2(pdb entry: 6cox) enzymes docked with novel ligands were evaluated for binding energies. Lead optimization was performed by computational simulation: methoxy-substituted analogues displayed the highest negative ligand–protein-binding energies. These results prompted us to evaluate in vivo anti-inflammatory activity by
carrageenan-induced paw oedema test in rats at a dose of 100 mg/kg. Ibuprofen was administered as standard drug. Lead compounds having significant activity were tested for in vitro cyclooxygenase isoenzyme inhibition assay and found to be more selective towards COX-2 as indicated by COX-2 selective index. The objective of our research is to accept the challenge of discovery of new drug. To ensure the desired target specificity and potency, bioavailability and lack of toxicity, our approach stems out lead generation from virtual screening to their synthesis and ends up with biological assays. Keywords Cyclooxygenase enzyme I and II Anti-inflammatory inhibitors Dihydropyrimidines Computational simulation Selective index
Introduction R. Dhankar Department of Chemistry, Sardar Patel Mahavidyalaya, Ganjward, Chandrapur 442402, Maharashtra, India A. M. Rahatgaonkar (&) Department of Chemistry, Institute of Science, Civil Lines, Nagpur 440001, Maharashtra, India e-mail: [email protected] R. Shukla Central Drug Research Institute, Lucknow 226001, Uttar Pradesh, India M. Chorghade Chorghade Enterprises, 14 Carlson Circle, Natick, MA, USA A. Tiwari (&) Biosensors and Bioelectronics Centre, Institute of Physics, Chemistry and Biology, Linko¨ping University, 58183 Linko¨ping, Sweden e-mail: [email protected]
Nonsteroidal anti-inflammatory drugs (NSAIDs) inhibit the enzymatic mechanism of cyclooxygenase (COX) enzyme responsible for transformation of arachidonic acid to prostaglandin H2. Prostaglandins are recognized for inflammation, fever and pain (Dannhart and Kiefer, 2001). In recent years, two forms of COX enzymes have been recognized as COX-
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