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<p>Inflammation, a key element of innate immunity, is more often than not regulated by the COX enzymes, mainly the inducible isoform, COX-2, which is overexpressed in a multitude of pathological states, such as neuroinflammation, cancer, among others. While selective COX-2 inhibitors (COXIBs), such as celecoxib, were designed to provide anti-inflammatory benefits with less severe gastrointestinal side effects of the non-selective NSAIDs, there are still issues about increased cardiovascular risk that highlight the need to identify safer, more selective inhibitory scaffolds. In this work, we examine the potential of PQA-18, a new prenylated quinoline carboxylic acid with a strong immunosuppressive activity and distinct PAK2 kinase inhibitory profile, to act as a COX-2 inhibitor based on its quinoline core structure, which aligns it with other known selective COX-2 inhibitors. We characterized PQA-18 in a multi-pronged approach by in silico (Density Functional Theory (DFT), molecular docking, and 100 ns Molecular Dynamics (MD) simulations) and in vitro COX-2 inhibition assays. Molecular docking revealed a remarkable stability between COX-2 and PQA-18, with a predicted binding affinity of 7.13 ± 0.183&#xa0;kcal/mol, which is higher than the reference standard, celecoxib with a binding affinity. This higher affinity can be attributed to PQA-18’s strong binding properties, in which it forms five Pi-Alkyl hydrophobic contacts that allow it to fit perfectly into the COX-2 channel, in contrast with celecoxib’s one Pi-Alkyl bond. In addition, MD simulations confirmed PQA-18 as the best conformational stabilizer, as it kept the lowest RMSD 0.15 to 0.45&#xa0;nm and persistent hydrogen bonding throughout the trajectory, while the celecoxib: COX-2 complex exhibited structural drift and transient interactions. PQA-18’s electronic structure was well balanced (ΔE = 1.85&#xa0;eV) and it had a strong electron acceptor potential (Electrophilicity index 7.98&#xa0;eV), as evidenced by the DFT calculations, which strengthened its possibility for robust charge-transfer complexation. To further validate these computational results in vitro assays also demonstrated that PQA-18 was effective as a monotherapy, with an IC<sub>50</sub> of ~ 2.4 µM and a maximum of 70% inhibition, strongly suggesting it as a potent therapeutic option. The above data support PQA-18 as a very promising lead compound with significantly improved COX-2 structural stabilization and thus provide a strong implied rationale for novel anti-inflammatory drug design.</p>

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Cyclooxygenase-2 (COX-2) inhibitory potential of prenylated quinoline carboxylic acid derivative (PQA-18): in silico, DFT and in vitro analysis

  • 期刊论文

  • 发表日期：

    2026年4月15日

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  • Nil Patil,
  • Mukul Jain

摘要

Inflammation, a key element of innate immunity, is more often than not regulated by the COX enzymes, mainly the inducible isoform, COX-2, which is overexpressed in a multitude of pathological states, such as neuroinflammation, cancer, among others. While selective COX-2 inhibitors (COXIBs), such as celecoxib, were designed to provide anti-inflammatory benefits with less severe gastrointestinal side effects of the non-selective NSAIDs, there are still issues about increased cardiovascular risk that highlight the need to identify safer, more selective inhibitory scaffolds. In this work, we examine the potential of PQA-18, a new prenylated quinoline carboxylic acid with a strong immunosuppressive activity and distinct PAK2 kinase inhibitory profile, to act as a COX-2 inhibitor based on its quinoline core structure, which aligns it with other known selective COX-2 inhibitors. We characterized PQA-18 in a multi-pronged approach by in silico (Density Functional Theory (DFT), molecular docking, and 100 ns Molecular Dynamics (MD) simulations) and in vitro COX-2 inhibition assays. Molecular docking revealed a remarkable stability between COX-2 and PQA-18, with a predicted binding affinity of 7.13 ± 0.183 kcal/mol, which is higher than the reference standard, celecoxib with a binding affinity. This higher affinity can be attributed to PQA-18’s strong binding properties, in which it forms five Pi-Alkyl hydrophobic contacts that allow it to fit perfectly into the COX-2 channel, in contrast with celecoxib’s one Pi-Alkyl bond. In addition, MD simulations confirmed PQA-18 as the best conformational stabilizer, as it kept the lowest RMSD 0.15 to 0.45 nm and persistent hydrogen bonding throughout the trajectory, while the celecoxib: COX-2 complex exhibited structural drift and transient interactions. PQA-18’s electronic structure was well balanced (ΔE = 1.85 eV) and it had a strong electron acceptor potential (Electrophilicity index 7.98 eV), as evidenced by the DFT calculations, which strengthened its possibility for robust charge-transfer complexation. To further validate these computational results in vitro assays also demonstrated that PQA-18 was effective as a monotherapy, with an IC50 of ~ 2.4 µM and a maximum of 70% inhibition, strongly suggesting it as a potent therapeutic option. The above data support PQA-18 as a very promising lead compound with significantly improved COX-2 structural stabilization and thus provide a strong implied rationale for novel anti-inflammatory drug design.