{
  "abstract": "Lead optimization in structure-based drug design aims to improve target binding while avoiding unintended interactions with off-target pockets. However, existing affinity-driven methods do not explicitly control specificity, whereas current specificity-aware approaches commonly require prior knowledge of off-target structures. We address off-target-agnostic specificity-aware lead optimization by analyzing the geometric mismatch between a ligand and the target pocket. We provide a conservative specificity lower bound for geometrically separated off-targets without requiring access to off-target structures. By metricizing pocket--ligand mismatch, the triangle inequality shows that reducing target--ligand mismatch improves a conservative lower bound on mismatch to a separated off-target class, which can be translated into a specificity lower bound through an empirical geometry--affinity calibration. Motivated by this analysis, we introduce SurfSpec, an off-target-agnostic lead optimization framework that iteratively grows ligands toward under-occupied regions of the target pocket surface. SurfSpec alternates between linker generation toward selected target-surface patches, which provides geometric pseudo-labels, and refinement under a pocket-conditioned ligand prior, which restores these pseudo-labels into valid ligands. On the CrossDocked2020 test set, SurfSpec reduces geometric mismatch and outperforms evaluated off-target-agnostic lead optimization baselines in empirical specificity, while maintaining competitive target-affinity improvement.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": null,
  "arxiv": "2609.02963",
  "author_total": 8,
  "authors": [
    {
      "name": "Minyeong Hwang"
    },
    {
      "name": "Yoorim Gang"
    },
    {
      "name": "Ziseok Lee"
    },
    {
      "name": "Wooyeol Lee"
    },
    {
      "name": "Young Bin Park"
    },
    {
      "name": "Jae-Mun Choi"
    },
    {
      "name": "Kyungsu Kim"
    },
    {
      "name": "Eunho Yang"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/41axjft0r23cy.bib",
  "cited_by": 0,
  "doi": "10.48550/arxiv.2609.02963",
  "fulltext_url": null,
  "id": "41axjft0r23cy",
  "issns": [],
  "landing_url": "https://arxiv.org/abs/2609.02963",
  "language": null,
  "licence": "CC-BY-4.0",
  "licence_label": "CC BY 4.0",
  "licence_source": "article",
  "licence_url": "http://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": "CC0-1.0",
  "native_subjects": [
    [
      "arxiv",
      "cs.LG"
    ],
    [
      "arxiv",
      "q-bio.QM"
    ],
    [
      "openalex",
      "1703|Computational Drug Discovery Methods"
    ]
  ],
  "openalex": "W7208730566",
  "pdf_url": "https://arxiv.org/pdf/2609.02963",
  "pmcid": null,
  "pmid": null,
  "published": "2026-09-02",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/41axjft0r23cy.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:18:37Z",
      "native_id": "2609.02963",
      "source": "arxiv",
      "url": "https://arxiv.org/abs/2609.02963"
    }
  ],
  "subjects": [
    {
      "field": "biology",
      "origin": "arxiv:q-bio.QM",
      "subfield": "bioinformatics"
    }
  ],
  "title": "SurfSpec: Enhancing Off-Target-Agnostic Specificity by Bounding Pocket-Ligand Geometric Mismatch",
  "title_text": "SurfSpec: Enhancing Off-Target-Agnostic Specificity by Bounding Pocket-Ligand Geometric Mismatch",
  "type": "preprint",
  "updated_at": "2026-10-30T12:18:37Z",
  "url": "https://research.draconitic.com/paper/41axjft0r23cy",
  "venue": "arXiv",
  "versions": []
}