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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-6950</article-id>
      <article-id pub-id-type="doi">10.51847/ynJWxXwyK3</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Original research</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Can Foundation Models Generate Pharmacological Hypotheses That Are Mechanistically Coherent, Falsifiable, and Worth Testing?</article-title>
      </title-group>
                    <contrib-group>
                      <contrib contrib-type="author">
              <name>
                <surname>Lefevre</surname>
                <given-names>Philippe</given-names>
              </name>
                              <xref rid="aff1" ref-type="aff">1</xref>
                                                            <xref rid="cor1" ref-type="corresp" />
                          </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Schmidt</surname>
                <given-names>Helga</given-names>
              </name>
                              <xref rid="aff2" ref-type="aff">2</xref>
                                        </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Fischer</surname>
                <given-names>Thomas</given-names>
              </name>
                              <xref rid="aff3" ref-type="aff">3</xref>
                                        </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Robert</surname>
                <given-names>Anne-Catherine</given-names>
              </name>
                              <xref rid="aff4" ref-type="aff">4</xref>
                                        </contrib>
                  </contrib-group>
                  <aff id="aff1">
            <label>1</label>Department of Foundation Models and Pharmacological Hypothesis Generation, Faculty of Pharmaceutical Sciences, University of Strasbourg, Strasbourg, France.
          </aff>
                  <aff id="aff2">
            <label>2</label>Department of Mechanistic Coherence in Hypothesis Generation, Faculty of Pharmacy, University of Freiburg, Freiburg, Germany.
          </aff>
                  <aff id="aff3">
            <label>3</label>Department of Falsifiability and Testability in AI, Faculty of Pharmacy, University of Zurich, Zurich, Switzerland.
          </aff>
                  <aff id="aff4">
            <label>4</label>Department of Hypothesis Worth Testing and Validation, Faculty of Pharmacy, University of Avignon, Avignon, France.
          </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="philippe.lefevre@unistra.fr">philippe.lefevre@unistra.fr</email>
                          </corresp>
          </author-notes>
                    <pub-date pub-type="epub">
        <day>28</day>
        <month>10</month>
        <year>2025</year>
      </pub-date>
      <volume>16</volume>
      <issue>5</issue>
      <fpage>88</fpage>
      <lpage>98</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>Foundation models can produce scientifically fluent accounts of targets, pathways, compounds, and disease mechanisms, but linguistic plausibility does not establish that an output constitutes a pharmacological hypothesis. A decision-worthy hypothesis must specify a directional intervention–mechanism–outcome relationship, identify the biological and experimental context in which the claim applies, expose assumptions and contradictory evidence, and state observations that could count against it. This Original Hypothesis-Generation Theory Article develops a conceptual framework for evaluating whether foundation-model outputs are mechanistically coherent, falsifiable, novel, experimentally discriminating, and consequential for pharmaceutical decision-making. The proposed contribution rejects the use of any single performance measure as a sufficient indicator of hypothesis quality. Instead, it treats quality as a structured profile comprising evidentiary grounding, mechanistic specification, falsifiability, scientific novelty, experimental feasibility, uncertainty, expected information gain, and decision consequence. The framework distinguishes prediction from explanation, association from mechanism, model confidence from calibrated uncertainty, and molecular plausibility from synthesizability, developability, safety, and therapeutic value. It further proposes that minimum evidentiary and falsifiability conditions should operate as non-compensatory gates: high fluency, novelty, or predicted activity cannot offset the absence of a traceable mechanism or an experiment capable of challenging the claim. The article outlines how molecular structures, biological networks, literature evidence, alternative hypotheses, and experimental constraints can be integrated into an auditable hypothesis object and evaluated prospectively. The framework remains theoretical and requires domain-specific, leakage-resistant, blinded, and experimentally grounded validation. Its purpose is not to authorize autonomous discovery decisions, but to define the conditions under which machine-generated propositions may become scientifically interpretable candidates for testing.</p>
      </abstract>
      <kwd-group>
                <kwd>Foundation models</kwd>
                <kwd>Pharmacological hypothesis generation</kwd>
                <kwd>Mechanistic coherence</kwd>
                <kwd>Falsifiability</kwd>
                <kwd>Experimental design</kwd>
                <kwd>Evidence grounding</kwd>
              </kwd-group>
    </article-meta>
  </front>
</article>