Odorant receptors (ORs) are highly sensitive receptors that respond to a diverse range of volatile compounds. While organisms relying on olfaction for survival possess remarkable abilities to detect trace chemicals, our current measurement techniques are inadequate in comparison. Traditionally, dogs have been trained to identify disaster survivors or diagnose illnesses by detecting trace chemicals. However, dog training is costly and time-consuming. Recent studies have shown significant differences in the chemical profiles of human breath between healthy individuals and those infected with pathogens such as malaria, tuberculosis, or COVID-19. Leveraging the unique chemical profiles associated with diseases could provide a robust method for disease detection. In this study, our objective is to engineer insect ORs to selectively activate in the presence of volatiles associated with diseases. Specifically, we focused on MhOR5, an odorant receptor from the Jumping Bristletail (Machilis hrabei), a basal insect that lacks the OR co-receptor (ORco) found in modern insects. MhOR5 is a well-characterized receptor with broad selectivity and an experimentally determined structure, making it an ideal candidate for targeted engineering. We expressed MhOR5 in a heterologous cell system using HEK293T cells and tested its response to disease-associated volatiles (DAVs). Through Rosetta ligand docking analysis, we identified key residues that potentially contribute to ligand selectivity. Subsequently, we generated mutants of MhOR5 by introducing specific residue mutations and evaluated their impact on receptor activation. Our findings revealed distinct ligand selectivity among most mutants in response to individual DAVs. This methodology establishes a solid foundation for engineering ORs with specificity towards particular chemicals and for developing engineered OR arrays for disease diagnosis. This work was funded by the Bill and Melinda Gates Foundation (BMGF INV-037981).