In silico Characterization of Taxifolin as a Dual Cyclooxygenase Ligand: Potential Role in Limiting Inflammation?
José Calado Quilenda, Sanseray da Silveira Cruz-Machado, Malu de Andrade Marques, Paulo Adenes Teixeira Coelho, João Gabriel Leite da Silva, Jonas Araújo de Sousa, Gabriela Alves do Nascimento, Francisco Bastos Cavalcante Sobrinho, Sacha Aubrey Alves Rodrigues Santos, Luzia Débora Saldanha Marques, Daniela Braga de Sousa, Maria Rayane Correia de Oliveira, Adriana Rolim Campos, Antônio Eufrásio Vieira-Neto, Francisco Ernani Alves Magalhães, Wagner Rodrigues de Assis SoaresIntroduction:
Inflammation is a fundamental physiological response. Currently available drugs, such as nonsteroidal anti-inflammatory drugs (NSAIDs), are effective, yet they present significant limitations, including gastrointestinal and hepatic toxicities alongside compromised safety during long-term administration. In this context, natural compounds with alternative pharmacological profiles have attracted increasing attention. Taxifolin, a flavanonol found in several plant species, has been suggested to possess anti-inflammatory properties. Therefore, the present study aimed to evaluate the in silico anti-inflammatory potential of taxifolin in comparison with therapeutically utilized NSAIDs.
Methods:
A total of 71 nonsteroidal anti-inflammatory drugs (NSAIDs) retrieved from the IUPHAR/BPS Guide to Pharmacology database were screened and compared with taxifolin through in silico molecular docking analyses targeting human cyclooxygenase isoforms COX-1 (PDB ID: 6Y3C) and COX-2 (PDB ID: 5IKQ). Ligand structures were prepared and optimized prior to docking using AutoDock Vina, with protocol validation performed through redocking analyses against co-crystallized ligands. Binding affinities, ligand-receptor interactions, and conformational stability within the catalytic pockets were evaluated. In addition, pharmacokinetic and toxicological properties were predicted using ADMET-based computational tools, including assessments of absorption, metabolism, cytochrome P450 interactions, clearance, and toxicity-related parameters. Zebrafish, in a carrageenaninduced inflammation model, were used to assess the in vivo toxicity and anti-inflammatory potential of the tested taxifolin.
Results:
Docking analyses demonstrated that taxifolin exhibits competitive binding affinities toward both cyclooxygenase isoforms, with interaction energies comparable to several clinically used NSAIDs. Favorable interactions were observed within the catalytic sites of both COX-1 and COX-2. ADMET predictions further indicated a favorable pharmacokinetic profile, including favorable gastrointestinal absorption and lower predicted toxicity compared with several synthetic NSAIDs. Taxifolin presented no signs of acute toxicity and demonstrated a significant effect in reducing carrageenan-induced inflammation.
Discussion:
The distinction between COX-1, a constitutive isoform associated with physiological homeostasis, and COX-2, an inducible isoform linked to pathological inflammation, has guided the development of anti-inflammatory drugs for decades. The ability of taxifolin to interact with the catalytic sites of both isoforms suggests a potential mechanism compatible with cyclooxygenase inhibition while maintaining a favorable predicted safety profile. These findings highlight the relevance of exploring natural flavonoids as molecular scaffolds for the development of new anti-inflammatory strategies.
Conclusion:
Taken together, this study supports taxifolin as a natural compound of translational interest with potential for the development of novel anti-inflammatory agents or semi-synthetic derivatives. However, further in vitro and in vivo studies are necessary to confirm its pharmacological activity and clinical applicability.