Abstract
Background: Arylindole derivatives are promising scaffolds in the design of new drugs. These scaffolds exhibit a wide biological activity, including inhibition of COX-2, antitumor activity, receptor GABA agonism, and estrogen receptor modulation.
Objectives: Taking this into account, this paper presents a study to understand the inhibitory action of certain 2-arylindole derivatives, specifically a series of 2,3-diarylindoles with IC50 values from 0.006 nM to 100 nM, on the COX-2 enzyme and supports its structural-activity relationship (SAR) through molecular docking simulations.
Methods: Applying molecular modelling, especially molecular docking, we assessed the SAR of a series of 2,3-arylindoles derivatives in the COX-2 enzyme.
Results: The results indicated that Gly 526 and Phe 381 residues are relevant for improving inhibitory activity on para-substituted 3-phenyl- compounds. Arg 120 was also demonstrated to be an important residue for COX-2 inhibition since it enables a π-cation interaction with the best compound in series A5 (experimental IC50 = 0.006 nM determined in advance). Furthermore, COX-2 presents flexibility in some regions of the active site to adequately accommodate 5-substituted compounds containing an indole ring.
Conclusion: Therefore, such structural features can be used as support for further Structural-Based Drug Design (SBDD) and/or Ligand-Based Drug Design (LBDD) studies on new selective COX-2 inhibitors.
Keywords: 2, 3-diarylindoles, COX-2 inhibitors, Molecular docking simulations, SAR, Drug design, Ligand interactions, Anti-inflammatory compounds.
[http://dx.doi.org/10.1186/s43094-020-00141-y]
[http://dx.doi.org/10.2174/1389557517666170807123201]
[http://dx.doi.org/10.1021/cr020033s]
[http://dx.doi.org/10.2174/092986712803341449]
[http://dx.doi.org/10.1038/nchembio.375]
[http://dx.doi.org/10.3390/ijms222413231]
[http://dx.doi.org/10.1021/bi026938h]
[http://dx.doi.org/10.1038/nrd1225]
[http://dx.doi.org/10.1146/annurev.biochem.69.1.145]
[http://dx.doi.org/10.1016/j.jaci.2013.10.057]
[http://dx.doi.org/10.1016/S0968-0896(03)00046-4]
[http://dx.doi.org/10.4155/fmc-2018-0159]
[http://dx.doi.org/10.1021/jm950664x]
[http://dx.doi.org/10.1042/bj3570709]
[http://dx.doi.org/10.1002/jcc.20084]
[http://dx.doi.org/10.1038/384644a0]
[http://dx.doi.org/10.1107/S2053230X16014230]
[http://dx.doi.org/10.1021/jm0209376]
[http://dx.doi.org/10.1021/jm020198t]
[http://dx.doi.org/10.3390/molecules22091507]