{
  "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).",
  "abstract_shown": true,
  "affiliations": [
    "Vector Institute for Artificial Intelligence, W1140-108 College St., Toronto, ON, Canada, M5G 0C6",
    "Department of Chemistry, University of Toronto, 80 St. George St., Toronto, ON, Canada, M5S 3H6",
    "Acceleration Consortium, 700 University Ave., Toronto, ON, Canada, M7A 2S4",
    "Department of Computer Science, University of Toronto, 40 St. George St., Toronto, ON, Canada, M5S 2E4",
    "Canadian Institute for Advanced Research (CIFAR), 661 University Ave., Toronto, ON, Canada, M5G 1M1",
    "Department of Chemical Engineering & Applied Chemistry, University of Toronto, 200 College St., Toronto, ON, M5S 3E5",
    "Department of Materials Science & Engineering, University of Toronto, 184 College St., Toronto, ON, M5S 3E4",
    "Institute of Medical Science, University of Toronto, 1 King’s College Circle, Toronto, ON, M5S 1A8",
    "NVIDIA, 431 King St. W #6th, Toronto, ON, M5V 1K4"
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "affs": [
        0,
        1
      ],
      "name": "Sven M. Papidocha",
      "orcid": "0009-0000-6375-5185"
    },
    {
      "affs": [
        1
      ],
      "name": "Yoshihiro Ogura",
      "orcid": "0009-0002-5079-9319"
    },
    {
      "affs": [
        1
      ],
      "name": "Jiahe Ren"
    },
    {
      "affs": [
        1
      ],
      "name": "Mikhail Saykin"
    },
    {
      "affs": [
        2
      ],
      "name": "Stuart Green",
      "orcid": "0000-0002-2960-9683"
    },
    {
      "affs": [
        3
      ],
      "name": "Varinia Bernales",
      "orcid": "0000-0002-8446-7956"
    },
    {
      "affs": [
        0,
        1,
        2,
        3,
        4,
        5,
        6,
        7,
        8
      ],
      "name": "Alán Aspuru-Guzik",
      "orcid": "0000-0002-8277-4434"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/0m03xh1zsdpsb.bib",
  "cited_by": 0,
  "doi": "10.26434/chemrxiv.15010755/v1",
  "fulltext_url": null,
  "id": "0m03xh1zsdpsb",
  "issns": [],
  "landing_url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010755/v1",
  "language": null,
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1703|Computational Drug Discovery Methods"
    ]
  ],
  "openalex": "W7223138103",
  "pdf_url": "https://chemrxiv.org/doi/pdf/10.26434/chemrxiv.15010755/v1",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-21",
  "publisher": "American Chemical Society (ACS)",
  "ris": "https://research.draconitic.com/paper/0m03xh1zsdpsb.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:24Z",
      "native_id": "10.26434/chemrxiv.15010755",
      "source": "chemrxiv",
      "url": "https://chemrxiv.org/doi/full/10.26434/chemrxiv.15010755/v1"
    }
  ],
  "subjects": [
    {
      "field": "chemistry",
      "origin": "source:chemrxiv",
      "subfield": "general"
    }
  ],
  "title": "Discovery of Nanomolar CDK2 Inhibitors Using Boltz-2",
  "title_text": "Discovery of Nanomolar CDK2 Inhibitors Using Boltz-2",
  "type": "preprint",
  "updated_at": "2026-10-30T12:17:24Z",
  "url": "https://research.draconitic.com/paper/0m03xh1zsdpsb",
  "venue": "ChemRxiv",
  "versions": []
}