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  <front>
    <journal-meta>
      <journal-id journal-id-type="iso-abbrev">Pharmacophore</journal-id>
      <journal-id journal-id-type="publisher-id">pharmacophorejournal.com</journal-id>
      <journal-id journal-id-type="publisher-id">Pharmacophore</journal-id>
      <journal-title-group>
        <journal-title>Pharmacophore</journal-title>
      </journal-title-group>
      <issn pub-type="epub">2229-5402</issn>
    </journal-meta>
    <article-meta>
      <article-id pub-id-type="publisher-id">pharmacophorejournal.com-6911</article-id>
      <article-id pub-id-type="doi">10.51847/JR4VTce12r</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Original research</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Generative Models for PROTAC Linker Design Using Ternary Complex Geometry and Degradation Data</article-title>
      </title-group>
                    <contrib-group>
                      <contrib contrib-type="author">
              <name>
                <surname>Wright</surname>
                <given-names>Ethan</given-names>
              </name>
                              <xref rid="aff1" ref-type="aff">1</xref>
                                        </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Bennett</surname>
                <given-names>Chloe</given-names>
              </name>
                              <xref rid="aff1" ref-type="aff">1</xref>
                                                            <xref rid="cor1" ref-type="corresp" />
                          </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Turner</surname>
                <given-names>Jack</given-names>
              </name>
                              <xref rid="aff2" ref-type="aff">2</xref>
                                        </contrib>
                  </contrib-group>
                  <aff id="aff1">
            <label>1</label>Department of Pharmaceutical AI Analytics, Faculty of Pharmacy, University of Leeds, Leeds, United Kingdom.
          </aff>
                  <aff id="aff2">
            <label>2</label>Department of Computational Drug Systems, Faculty of Medicine, University of Sheffield, Sheffield, United Kingdom.
          </aff>
                          <author-notes>
            <corresp id="cor1">
              <bold>Address for correspondence:</bold> Prof. Wael Abu Dayyih, Department of
              Pharmaceutical Chemistry, Faculty of Pharmacy, Mutah University, Al-Karak 61710, Jordan.
                              E-mail: <email xlink:href="chloe.bennett@gmail.com">chloe.bennett@gmail.com</email>
                          </corresp>
          </author-notes>
                    <pub-date pub-type="epub">
        <day>28</day>
        <month>06</month>
        <year>2026</year>
      </pub-date>
      <volume>17</volume>
      <issue>3</issue>
      <fpage>123</fpage>
      <lpage>131</lpage>
      <permissions>
        <copyright-statement>
          Copyright: &#x000a9; 2026 Pharmacophore
        </copyright-statement>
        <copyright-year>2026</copyright-year>
        <license>
          <ali:license_ref xmlns:ali="http://www.niso.org/schemas/ali/1.0/"
            specific-use="textmining" content-type="ccbyncsalicense">
            https://creativecommons.org/licenses/by-nc-sa/4.0/</ali:license_ref>
          <license-p>This is an open access journal, and articles are distributed under the terms of
            the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows
            others to remix, tweak, and build upon the work non-commercially, as long as appropriate
            credit is given and the new creations are licensed under the identical terms.</license-p>
        </license>
      </permissions>
      <abstract>
        <title>A<sc>BSTRACT</sc></title>
        <p>PROTACs are bifunctional therapeutic agents that achieve selective protein degradation by recruiting a target protein to an E3 ligase, with the linker connecting the two ligands serving as a critical determinant of ternary complex formation, cellular activity, and degradation efficacy. Current linker design is largely empirical, relying on iterative synthesis of chemically familiar linkers, which constrains the exploration of broader chemical space and slows the discovery of PROTACs with optimal geometry and degradation profiles. To address this, we propose a generative chemistry framework for PROTAC linker design that leverages ternary complex structural information and degradation activity annotations to produce linkers compatible with both molecular geometry and pharmacological intent. Conditional generative models, such as diffusion models or variational autoencoders, can be trained on PROTAC structures paired with degradation metrics like DC50 and Dmax, and conditioned during generation on the protein of interest, E3 ligase, warhead structures, ternary complex geometry, and desired degradation profile. The resulting linkers are expected to be chemically valid, compatible with the two warheads, and consistent with stereochemical constraints derived from ternary complex models, preserving key binding interactions while enabling productive POI–E3 proximity. By moving beyond empirical variation, structure-informed and degradation-aware generative design could accelerate PROTAC development and enable systematic exploration of linker space for targeted protein degradation.</p>
      </abstract>
      <kwd-group>
                <kwd>PROTACs</kwd>
                <kwd>Generative chemistry</kwd>
                <kwd>Linker design</kwd>
                <kwd>Ternary complex</kwd>
                <kwd>Targeted protein degradation</kwd>
                <kwd>Diffusion models</kwd>
              </kwd-group>
    </article-meta>
  </front>
</article>