A series of conformationally constrained new Propionic acid derivatives were subjected to a synergistic integration of docking and quantitative structure-activity relationship (QSAR) techniques to optimize non-steroidal anti-inflammatory agents (NSAIDs). Examining the particular conditions for COX-2 inhibition selectivity among these congeners as selective cyclooxygenase-2 (COX-2) inhibitors was the aim of the study. The combination of these methodologies accelerates the identification and optimization of lead compounds, facilitating efficient prediction and screening of compound libraries. This integrated approach not only expedites drug discovery but also provides a rational foundation for the design of novel molecules with desired pharmacological activities, particularly in the context of NSAIDs and similar therapeutic agents