Álex Pérez-Sánchez

Despite their extensive use, the therapeutic potential of nonsteroidal anti-inflammatory drugs (NSAIDs) remains significantly constrained by adverse side effects. This limitation primarily arises from insufficient selectivity, as current NSAIDs inhibit not only the inducible cyclooxygenase-2 (COX-2) isoform at sites of inflammation but also constitutive COX-2 in healthy tissues and, frequently, cyclooxygenase-1. To address this challenge, we developed photoswitchable NSAIDs that combine COX-2 selectivity with light-controlled activity to enable spatiotemporal confinement of the therapeutic effect at inflamed tissues. Following computational design and screening of a library of azoaromatic derivatives of celecoxib─the most widely used COX-2 selective NSAID─three photoswitchable analogues were synthesized, which exhibited reversible and efficient trans-cis photoconversion. Light-controlled and selective COX-2 inhibition was demonstrated for these compounds in vitro, reaching up to 5-fold potency enhancement in macrophage assays upon photoisomerization from the initial, dark-adapted trans isomer to the cis state. The best candidate displayed in vivo efficacy in a zebrafish model of acute inflammation, where administration of the photoinduced cis form reduced leukocyte recruitment at the wound site. These findings position photoswitchable NSAIDs as a promising alternative to conventional drugs for treating inflammation and related conditions, including cancer.

This dataset contains the replication data for the study "Photoswitchable COX-2-Selective Inhibitors as Light-Regulated Anti-Inflammatory Agents", covering computational, synthetic, photochemical, biochemical, and in vivo experimental data generated between 2020 and 2026. The computational data includes molecular docking (GOLD), molecular dynamics simulations (AMBER), MM-PBSA binding free energies, and TD-DFT calculations (Gaussian) for seven photocoxib (PC1–PC7) analogues derived from celecoxib by azologization. Synthetic and characterization data comprise raw and processed Bruker NMR spectra (1H, 13C, COSY, HSQC, HMBC, NOESY), IR spectra, and high-resolution mass spectrometry (HRMS) reports for the three synthesized candidates (PC4, PC5, PC6). Photochemical data include UV-vis absorption spectra, photoisomerization quantum yields, thermal half-lives, fatigue resistance profiles, and glutathione stability assays documenting the reversible trans–cis photoswitching behavior of the compounds under UV (365 nm) and visible light (405 or 445 nm). Biochemical and cell biology data encompass fluorometric COX-1 and COX-2 enzyme inhibition assays, ELISA-based prostaglandin E2 (PGE2) production measurements in J774 murine macrophage cultures, and MTT cell viability assays comparing trans and cis isomers. In vivo data consist of Sudan Black-stained fluorescence microscopy images and leukocyte count spreadsheets from a zebrafish tailfin amputation model of acute inflammation, organized across multiple treatment conditions and experimental batches. Data are provided in ten file formats including .pdb, .inpcrd/.prmtop, .fid (Bruker NMR), .dat/.log, .xlsx, .tif, .jpg, and .pdf.

Allosteric structural communication path between the NANQ-IMC6 ligands in monomer A and monomer B of the homodimer of human Cyclooxygenase-2. For details, see: Álex Pérez-Sánchez, et al., Protein Science, 2024.

This dataset contains simulation results and analyses related to the fluorescence modulation of a COX-2 specific fluorogenic probe.

The MolBioMed research group of the Department of Chemistry, in collaboration with the University of Barcelona, has published a study that demonstrates the direct relationship between the COX-2 dimer and cancer. The computational study shows the different behavior of the fluorescence spectrum of the NANQ-IMC6 compound when interacting with the monomer (present in inflamed tissues) and with the dimer (present in cancer cells).

Cyclooxygenase-2 (COX-2) plays a crucial role in inflammation and has been implicated in cancer development. Understanding the behavior of COX-2 in different cellular contexts is essential for developing targeted therapeutic strategies. In this study, we investigate the fluorescence spectrum of a fluorogenic probe, NANQ-IMC6, when bound to the active site of human COX-2 in both its monomeric and homodimeric forms. We employ a multiscale first-principles simulation protocol that combines ground state MM-MD simulations with multiple excited state adiabatic QM/MM Born-Oppenheimer MD simulations based on linear response TD-DFT, which allows to account for protein heterogeneity effects on excited-state properties. Emission is then estimated from polarizable embedding TD-DFT QM/MMPol calculations. Our findings indicate that the emission shift arises from dimerization of the highly overexpressed COX-2 in cancer tissues, in contrast to the monomer structure present in inflammatory lesions and in normal cells with constitutive COX-2. This spectral shift is linked to changes in specific protein–probe interactions upon dimerization due to changes in the environment, whereas steric effects related to modulation of the NANQ geometry by the protein scaffold are found to be minor. This research paves the way for detailed investigations on the impact of environment structural transitions on the spectral properties of fluorogenic probes. Moreover, the fact that COX-2 exists as homodimer just in cancer tissues, but as monomer elsewhere, gives novel hints for therapeutical avenues to fight cancer and contributes to the development of drugs targeted to COX-2 dimer in cancer, but without affecting constitutive COX-2, thus minimizing off-target effects.