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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-6878</article-id>
      <article-id pub-id-type="doi">10.51847/TzZy4qWv97</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Original research</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Molecular Foundation Models for Lead Optimization Using Bioactivity, ADMET, and Synthetic Feasibility Prompts</article-title>
      </title-group>
                    <contrib-group>
                      <contrib contrib-type="author">
              <name>
                <surname>Novak</surname>
                <given-names>Peter</given-names>
              </name>
                              <xref rid="aff1" ref-type="aff">1</xref>
                                                            <xref rid="cor1" ref-type="corresp" />
                          </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Svoboda</surname>
                <given-names>Jana</given-names>
              </name>
                              <xref rid="aff1" ref-type="aff">1</xref>
                                        </contrib>
                  </contrib-group>
                  <aff id="aff1">
            <label>1</label>Department of Drug Discovery Informatics, Faculty of Pharmacy, Charles University, Prague, Czech Republic.
          </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="peter.novak@gmail.com">peter.novak@gmail.com</email>
                          </corresp>
          </author-notes>
                    <pub-date pub-type="epub">
        <day>28</day>
        <month>02</month>
        <year>2026</year>
      </pub-date>
      <volume>17</volume>
      <issue>1</issue>
      <fpage>53</fpage>
      <lpage>61</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>Lead optimization involves the simultaneous enhancement of potency, ADMET properties, and synthetic feasibility, making the progression from an initial hit or lead to a viable drug candidate a challenging multi-objective design problem. Traditional medicinal chemistry workflows remain iterative, expert-intensive, and reliant on repeated cycles of design, synthesis, and testing, while existing molecular generative models often target single-property optimization or employ reward functions that, though powerful, are not always intuitive for medicinal chemists to guide. To address these limitations, this article proposes a molecular foundation model for prompt-conditioned lead optimization, designed to generate optimized lead molecules from natural-language or structured prompts specifying desired bioactivity, ADMET, and synthetic feasibility constraints. The system leverages a pre-trained transformer-based molecular language model fine-tuned for conditional generation, where a prompt encoder directs molecule generation toward the requested target profile, and reinforcement learning aligns outputs with bioactivity, ADMET, and synthesis-oriented reward signals. The model aims to produce a small, diverse set of chemically valid candidates tailored to the prompt rather than an exhaustive random library, providing medicinal chemists with a curated selection for review. By combining chemical language modeling with multi-objective reward design, prompt-conditioned molecular foundation models have the potential to make lead optimization more interactive, transparent, and parallelizable, supporting more efficient exploration of drug-like chemical space.</p>
      </abstract>
      <kwd-group>
                <kwd>Molecular foundation models</kwd>
                <kwd>Generative chemistry</kwd>
                <kwd>Prompt-conditioned generation</kwd>
                <kwd>Lead optimization</kwd>
                <kwd>ADMET</kwd>
                <kwd>Synthetic feasibility</kwd>
              </kwd-group>
    </article-meta>
  </front>
</article>