Project Abstract Targeted covalent inhibitors (TCI) represent a powerful but underexploited chemistry for targeting challenging and uncharacterized protein structures, especially therapeutically relevant targets. Among the many electrophilic warheads capable of modifying proteins, sulfonyl-fluoride exchange chemistry (SuFEx) are among the most chemically versatile. SuFEx combines high modification yields with broad cellular proteome coverage due to the targeting of Lys, Tyr, Ser, and His residues that are abundant among viral, bacterial, and eukaryotic proteomes (i.e., compared with the relatively low abundance of cysteines targeted by most other warheads). Given the broad coverage by SuFEx warheads, they would be an invaluable tool to target HIV-1 protein targets as well as their interactions with cellular proteins, where reactive cysteines may be absent. Despite the great potential of SuFEx warheads as chemical probes, and efforts from both academia and industry to develop the methodology, they are heavily underexploited given that the breadth of their intrinsic chemical reactivity has not been fully characterized and cataloged. Thus, there is a need to determine SuFEx chemistry intrinsic reactivity to allow the development of predictive models. This information can be used to design SuFEx warheads to provide the appropriate activity for covalent modification. This proposal seeks to address this need by experimentally determining the intrinsic reactivity of a large number of SuFEx probes, spanning the largest commercially available chemical space, and to develop quantum mechanics and machine learning models to predict these reactivities in a drug/probe design setting. A prospective virtual screen incorporating this information will be performed against HIV CA, leading to new chemical matter in a novel ligand class against this protein.