Year: 2026
Type: preprint
Abstract: The computational design of small-molecule ligands for pharmaceutical targets has historically been hindered by a strict trade-off between screening throughput and predictive accuracy. While next-generation cofolding affinity models like Boltz-2 hold immense promise for bridging this gap, their utility in prospective medicinal chemistry campaigns remains largely unexplored. To date, virtual screens leveraging these models have been overwhelmingly restricted to standard commercial catalogs, leaving their capacity to navigate novel, synthetically tailored chemical spaces unevaluated. Here, we present a novel hit discovery platform that integrates Boltz-2’s affinity module with a custom screening space of stereochemically complex tetrahydroquinolines, accessed efficiently via a single-step multicomponent approach. Boltz-2 successfully guided both the initial high-throughput virtual screening of these targeted scaffolds and subsequent hit optimization, rapidly yielding nanomolar inhibitors of cyclin-dependent kinase 2 (CDK2).
Source: ChemRxiv
Language: English
Subfield: Drug Discovery
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7223138103