122: Designing PAR-2 modulators through green click chemistry: Integrated computational and in vitro prioritization of 1,2,3-triazole peptides

Abstract: Cardiovascular diseases (CVD) remain the leading cause of mortality globally, which drives the identification of new therapeutic targets associated with chronic inflammatory processes. Among emerging targets, G-protein-coupled receptors (GPCRs) stand out, particularly protease-activated receptor 2 (PAR-2), whose activation promotes pro-inflammatory pathways involved in cardiovascular pathology and other inflammatory diseases. This paper presents an integrated strategy, applicable to medicinal chemistry, for the design and initial evaluation of PAR-2 modulators under a sustainable synthesis approach. A family of 1,2,3-triazole derivatives was designed and synthesized via a CuAAC click-chemistry route, prioritizing high-efficiency transformations and waste minimization in accordance with the 12 Principles of Green Chemistry. Spectroscopic techniques structurally characterized the compounds. To support the structure-property relationship and guide the selection of analogues, computational tools, including electronic calculations, molecular coupling, and molecular dynamics, were integrated to analyze the stability of complexes and relevant interactions at the atomic level. Biological assays addressed initial biological validation focused on PAR-2, including calcium mobilization, complemented by cell viability tests to rule out cytotoxicity of synthesized analogues. In accordance with the above, the research combines bioactive compound synthesis oriented toward green chemistry with computational evaluation and biological assays to provide a practical framework for generating and prioritizing candidates with potential applications in inflammation associated with CVD.