Identification and development of a small molecule probe for HNMT

National Center For Advancing Translational Sciences

Investigators

Abstract

During this reporting period, the collaborative team advanced lead optimization of the current series to enhance compound potency, selectivity, and in vitro ADME/Tox properties. X-ray co-crystal structure was solved at a CRO, providing critical insights for structure-based drug design. In parallel, the computational chemistry team implemented a virtual reaction enumeration strategy using commercially available Enamine building blocks to generate analog libraries of the lead series. Systematic predictions through AI/ML models combined with structure-based docking led to the discovery of a highly potent inhibitor with 11 nM activity. Additionally, a virtual screening campaign integrating machine learning and structure-based methods identified 316 hits, which were subsequently validated in experimental assays.