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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-6920</article-id>
      <article-id pub-id-type="doi">10.51847/yTsRGCqU2z</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Original research</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Mechanistic Plausibility before Predictive Performance: Reordering the Standards by Which Computational Pharmacology Models Are Judged</article-title>
      </title-group>
                    <contrib-group>
                      <contrib contrib-type="author">
              <name>
                <surname>Chen</surname>
                <given-names>Wei</given-names>
              </name>
                              <xref rid="aff1" ref-type="aff">1</xref>
                                                            <xref rid="cor1" ref-type="corresp" />
                          </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Tanaka</surname>
                <given-names>Yuki</given-names>
              </name>
                              <xref rid="aff2" ref-type="aff">2</xref>
                                        </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Lin</surname>
                <given-names>Mei</given-names>
              </name>
                              <xref rid="aff3" ref-type="aff">3</xref>
                                        </contrib>
                  </contrib-group>
                  <aff id="aff1">
            <label>1</label>Department of Mechanistic Pharmacology and Model Evaluation, College of Pharmaceutical Sciences, China Agricultural University, Beijing, China.
          </aff>
                  <aff id="aff2">
            <label>2</label>Department of Computational Pharmacology and Biological Reasoning, Graduate School of Pharmacy, University of Tokyo, Tokyo, Japan.
          </aff>
                  <aff id="aff3">
            <label>3</label>Department of Predictive Model Assessment, Faculty of Pharmacy, National University of Singapore, Singapore.
          </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="wei.chen@cau.edu.cn">wei.chen@cau.edu.cn</email>
                          </corresp>
          </author-notes>
                    <pub-date pub-type="epub">
        <day>28</day>
        <month>10</month>
        <year>2024</year>
      </pub-date>
      <volume>15</volume>
      <issue>5</issue>
      <fpage>80</fpage>
      <lpage>89</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>Computational pharmacology models are increasingly judged through predictive metrics that permit rapid comparison among algorithms but offer only partial evidence about pharmaceutical usefulness. A model may reproduce held-out observations while relying on unstable data associations, biologically implausible relationships, undocumented implementation choices, or causal interpretations that its design cannot support. This creates an unresolved methodological problem: predictive performance is often treated as the principal threshold of model quality even when the intended application requires explanation, mechanistic extrapolation, intervention reasoning, or consequential pharmaceutical decision support. This Original Methodological Position Article proposes a mechanism-first ordering of computational pharmacology evidence. The proposed position distinguishes structural coherence, biological coherence, and causal coherence from predictive adequacy and argues that these dimensions should be examined before performance results are granted substantive pharmaceutical meaning. Predictive evaluation remains necessary, but it is repositioned as a later test of an already scrutinized model rather than a substitute for plausibility, reproducibility, applicability, calibration, uncertainty characterization, or context-of-use specification. The article also introduces a bounded qualification logic in which the permissible influence of a model depends on the strength and relevance of its supporting evidence, the consequences of error, and the reversibility of the decision. The proposal is conceptual rather than empirically validated and does not establish a universal validation sequence, regulatory standard, clinical recommendation, or deployment criterion. Its purpose is to organize more defensible judgments about computational models and to clarify why benchmark success, mechanistic explanation, causal inference, experimental confirmation, and pharmaceutical utility must remain distinct evidentiary claims.</p>
      </abstract>
      <kwd-group>
                <kwd>Computational pharmacology</kwd>
                <kwd>Mechanistic plausibility</kwd>
                <kwd>Predictive adequacy</kwd>
                <kwd>Quantitative systems pharmacology</kwd>
                <kwd>Model credibility</kwd>
                <kwd>Causal coherence</kwd>
              </kwd-group>
    </article-meta>
  </front>
</article>