2,3-Diarylindoles as COX-2 Inhibitors: Exploring the Structure-activity Relationship through Molecular Docking Simulations.

Autor: Cuppoloni A; Department of Pharmacy, School of Pharmaceutical Sciences, University of Sao Paulo, São Paulo, Brazil., Silva JV; Department of Pharmacy, School of Pharmaceutical Sciences, University of Sao Paulo, São Paulo, Brazil., Snape TJ; Leicester School of Pharmacy, De Montfort University, Leicester, LE1 9BH, UK., Lal S; Amity Institute of Pharmacy, Samridhi Lal, Amity University, Gurugram, India., Giarolla J; Department of Pharmacy, School of Pharmaceutical Sciences, University of Sao Paulo, São Paulo, Brazil.
Jazyk: angličtina
Zdroj: Current topics in medicinal chemistry [Curr Top Med Chem] 2023; Vol. 23 (12), pp. 1081-1089.
DOI: 10.2174/1568026623666230207120752
Abstrakt: 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 IC 50 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 IC 50 = 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.
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Databáze: MEDLINE
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