Molecular Basis of Binding Interactions of NSAIDs and Computer-Aided Drug Design Approaches in the Pursuit of the Development of Cyclooxygenase-2 (COX-2) Selective Inhibitors

Abstract

The nonsteroidal anti-inlammatory drugs (NSAIDs) are important class of therapeutic agents used for the treatment of pain, inlammation and fever. Nonselective inhibition of cyclooxygenase (COX-1 and COX-2) isoenzymes by classical NSAIDs is associated with undesirable side efects such as gastrointestinal (GI) and renal toxicities due to COX-1 inhibition. To circumvent this problem, several COX-2 selective inhibitors were developed with superior GI safety proile. However, the voluntary market withdrawal of potent COX-2 selective inhibitors (rofecoxib and valdecoxib) due to their severe cardiovascular toxicity which is also found to be associated with some of the traditional NSAIDs suggesting the need to relook into the entire class of NSAIDs rather than exclusively victimizing the COX-2 selective inhibitors. Furthermore, the recent evidences for the involvement of COX-2 selective inhibitors in the aetiology of many diseases, such as Alzheimer's disease, Parkinson's disease, diabetes, various cancers and so on, have gained much atention for researchers to design and develop novel COX-2 selective inhibitors with improved pharmacodynamics and pharmacokinetic proile. This chapter is focused on the detailed analysis of molecular basis of binding interactions of various NSAIDs by highlighting the role of crucial amino acid residues at the binding site of cyclooxygenase enzymes (COXs) to be considered for selective inhibition of COX-2 enzyme while emphasising the impact of signiicant CADD strategies employed for designing new potent COX-2 inhibitors with tuned selectivity.

Molecular drug design and docking study of novel n- substituted celecoxib derivatives as selective cyclooxygenase-2 inhibitors

“…During the last two decades, many drugs manufacture pharmaceutical companies improves the selectivity of targeting COX-2 by developing several NSAIDs medications. The paramount objective of all these process is to decrease the inflammation and pain syndromes without missing the preservation of COX-1 enzyme in gastrointestinal tract, resulting to decrees a lot of side effects 4,5 . Among all these, Celebrex is the most effective COX-2 selective inhibitor which successfully remains for a years in the markets because the magnificent potency against several diseases including: ankylosing spondylitis, rheumatoid arthritis, and osteoarthritis 6 .…”

Revelation of New Compound from Ethanolic Extract of Fragaria x ananassa var. Lembang

“…, [159][160][161][162][163][164][165][166][167][168] that The trifluoromethyl group attached to the pyrazole ring is surrounded by a close hydrophobic cavity and strong electrostatic field with Arg120 (Deb, et al, 2017). Summarizing all of the evidence, we predict that the presence of pyrimidine and pyrazole on one structure of compound 3-Cyclopentyl-5-(1-hydroxyethyl)-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one promoted the potential chemopreventive activity.…”

DockStream: A Docking Wrapper to Enhance De Novo Molecular Design

“…6b that many of the top compounds contain the sulfonamide moiety which is present in the approved drugs, Celecoxib and Valdecoxib. 60,61 The maximally similar generated compound displays a Tanimoto similarity of 0.937 and shares both the sulfonamide moiety and the cis-stilbene scaffold with its corresponding known active (Fig. 7a).…”