BackgroundDrugs that inhibit cyclooxygenase-2 (COX-2) while sparing cyclooxygenase-1 (COX-1) represent a new attractive therapeutic development and offer new perspective for further use of COX-2 inhibitors. Intention of this work is to develop safer, selective COX-2 inhibitors that do not produce harmful effects.ResultsA series of 55 tyrosine derivatives were designed for evaluation as selective COX-2 inhibitors and investigated by in silico for their anti-inflammatory activities using C-Docker. The results of docking study showed that 35 molecules were found to selectively inhibit the enzyme COX-2. These molecules formed stable π hydrophobic and additional van der Waals interactions in the active site side pocket of COX-2. The molecules selected from docking studies were examined through ADMET descriptors and Osiris property explorer to find its safety profile as well. The tyrosine derivatives containing toxic fragments were eliminated.ConclusionThe results conclude that out of 55, 19 molecules possessed best binding energy (< −3.333 kcal/mol) and these molecules had more selective and safer COX-2 inhibitor profile compared to the standard celecoxib.Graphical abstract3-D structural interactions of COX-2 inhibiting tyrosine derivatives.
Molecular modelling uses theoretical and computational chemistry, which offers insight into the nature of molecular systems. This chapter highlights the theoretical explanation of molecular modelling methods and describes the designing of novel tyrosine COX-2 inhibitors using molecular modelling as an example. As a first step, fragment-based drug design is used to design the novel tyrosine analogues and ligand-based drug design such as QSAR, and pharmacophore was used to identify the descriptors, ensemble of steric and electronic features, which is responsible for the selective COX-2 inhibition. The next step, structure-based drug design, was used to analyses intra- and intermolecular interactions in the drug receptor system to improve the binding affinity and pharmacokinetic properties. Finally, the pharmacokinetic and toxicity properties were predicted quantitatively using rationalization of observed structure-activity relationships and the results are reported.
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