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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-6848</article-id>
      <article-id pub-id-type="doi">10.51847/Bl6094uJst</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Original research</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Generative Transformers for CYP3A4-Sparing Molecule Design Using ADMET and Synthetic Feasibility Constraints</article-title>
      </title-group>
                    <contrib-group>
                      <contrib contrib-type="author">
              <name>
                <surname>Huy</surname>
                <given-names>Nguyen Thanh</given-names>
              </name>
                              <xref rid="aff1" ref-type="aff">1</xref>
                                                            <xref rid="cor1" ref-type="corresp" />
                          </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Minh</surname>
                <given-names>Pham Quang</given-names>
              </name>
                              <xref rid="aff1" ref-type="aff">1</xref>
                                        </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Bich</surname>
                <given-names>Le Thi</given-names>
              </name>
                              <xref rid="aff2" ref-type="aff">2</xref>
                                        </contrib>
                  </contrib-group>
                  <aff id="aff1">
            <label>1</label>Department of Pharmaceutical Data Science, Faculty of Pharmacy, Vietnam National University, Hanoi, Vietnam.
          </aff>
                  <aff id="aff2">
            <label>2</label>Department of Intelligent Drug Analytics, Faculty of Medicine, Can Tho University, Can Tho, Vietnam.
          </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="huy.nguyen@gmail.com">huy.nguyen@gmail.com</email>
                          </corresp>
          </author-notes>
                    <pub-date pub-type="epub">
        <day>28</day>
        <month>02</month>
        <year>2025</year>
      </pub-date>
      <volume>16</volume>
      <issue>1</issue>
      <fpage>31</fpage>
      <lpage>39</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>CYP3A4 is a major metabolic enzyme that can profoundly affect the oral exposure and clearance of drug candidates, making the design of molecules that avoid excessive CYP3A4 metabolism while retaining favorable drug-like properties a central challenge in early discovery. Traditional medicinal chemistry typically addresses metabolic liability only after candidate structures have been synthesized, a reactive approach that complicates the simultaneous optimization of CYP3A4 sparing, broader ADMET behavior, and synthetic feasibility. To address this, a conceptual generative transformer framework is proposed for designing novel CYP3A4-sparing molecules, capable of producing chemically valid candidates while respecting ADMET and synthetic constraints. The approach involves fine-tuning a transformer-based molecular language model trained on drug-like SMILES using reinforcement learning, with conditional generation guided by property tokens representing CYP3A4-sparing intent, ADMET desirability, and synthetic accessibility preferences. This framework could generate focused candidate libraries predicted to minimize CYP3A4 liability while maintaining favorable pharmacokinetic and synthetic characteristics, which would then be assessed for novelty, chemical diversity, and alignment with the desired design profile. By proposing metabolically resilient molecular starting points, a CYP3A4-sparing generative transformer could support hit-to-lead and lead-optimization decisions, complementing medicinal chemistry expertise without replacing the need for experimental validation.</p>
      </abstract>
      <kwd-group>
                <kwd>Generative transformers</kwd>
                <kwd>CYP3A4</kwd>
                <kwd>ADMET</kwd>
                <kwd>Molecular generation</kwd>
                <kwd>Reinforcement learning</kwd>
                <kwd>Synthetic feasibility</kwd>
              </kwd-group>
    </article-meta>
  </front>
</article>