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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-6932</article-id>
      <article-id pub-id-type="doi">10.51847/16ujeGQHG1</article-id>
      <article-categories>
        <subj-group subj-group-type="heading">
          <subject>Original research</subject>
        </subj-group>
      </article-categories>
      <title-group>
        <article-title>Drug Candidate Has an Environmental Profile before It Becomes a Medicine: Sustainability-Aware Lead Optimization</article-title>
      </title-group>
                    <contrib-group>
                      <contrib contrib-type="author">
              <name>
                <surname>Dlamini</surname>
                <given-names>Nokuthula</given-names>
              </name>
                              <xref rid="aff1" ref-type="aff">1</xref>
                                                            <xref rid="cor1" ref-type="corresp" />
                          </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Zulu</surname>
                <given-names>Sipho</given-names>
              </name>
                              <xref rid="aff1" ref-type="aff">1</xref>
                                        </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Nkosi</surname>
                <given-names>Thabo</given-names>
              </name>
                              <xref rid="aff2" ref-type="aff">2</xref>
                                        </contrib>
                      <contrib contrib-type="author">
              <name>
                <surname>Molefe</surname>
                <given-names>Lerato</given-names>
              </name>
                              <xref rid="aff3" ref-type="aff">3</xref>
                                        </contrib>
                  </contrib-group>
                  <aff id="aff1">
            <label>1</label>Department of Environmental Profiling and Sustainability-Aware Lead Optimization, Faculty of Pharmacy, University of KwaZulu-Natal, Durban, South Africa.
          </aff>
                  <aff id="aff2">
            <label>2</label>Department of Green Chemistry and Drug Design, Faculty of Pharmacy, University of Cape Town, Cape Town, South Africa.
          </aff>
                  <aff id="aff3">
            <label>3</label>Department of Sustainable Drug Discovery, Faculty of Pharmaceutical Sciences, University of the Witwatersrand, Johannesburg, South Africa.
          </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="dlaminin@ukzn.ac.za">dlaminin@ukzn.ac.za</email>
                          </corresp>
          </author-notes>
                    <pub-date pub-type="epub">
        <day>28</day>
        <month>08</month>
        <year>2026</year>
      </pub-date>
      <volume>17</volume>
      <issue>4</issue>
      <fpage>13</fpage>
      <lpage>25</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>Pharmaceutical lead optimization traditionally integrates potency, selectivity, exposure, safety, physicochemical behavior, and synthetic feasibility, yet the environmental implications of a candidate are often considered only after substantial structural and process commitments have been made. This separation is scientifically problematic because molecular features selected during discovery can influence environmental transformation, persistence, mobility, bioaccumulation, ecotoxicological activity, manufacturing burden, and the properties of transformation products. This article develops Sustainability-Aware Lead Optimization as an original conceptual contribution for treating these consequences as a structured part of candidate design rather than as an end-stage annotation. The approach centers on a proposed Candidate Environmental Profile that preserves distinct evidence streams for environmental fate, ecological exposure and effects, therapeutic quality, synthesis, lifecycle burden, uncertainty, and decision provenance. The profile is intended to support multiobjective comparison, targeted evidence generation, and explicit governance gates without collapsing heterogeneous dimensions into a universal sustainability score. The synthesis shows why environmental performance cannot be inferred from a single descriptor, biodegradation result, hazard endpoint, or computational prediction, and why apparent environmental improvement may be offset by reduced therapeutic performance, increased dose, difficult synthesis, hazardous processing, or burden shifting across the lifecycle. The contribution remains conceptual: it does not establish predictive validity, regulatory acceptability, or operational readiness. Its value lies in defining the components, relationships, uncertainty labels, and decision boundaries that future prospective medicinal-chemistry programs can evaluate. Embedding such evidence earlier may help pharmaceutical discovery identify avoidable environmental liabilities while sufficient molecular and process flexibility remains to address them.</p>
      </abstract>
      <kwd-group>
                <kwd>Sustainable molecular design</kwd>
                <kwd>Lead optimization</kwd>
                <kwd>Environmental fate</kwd>
                <kwd>Pharmaceutical pollution</kwd>
                <kwd>Biodegradability</kwd>
                <kwd>Ecotoxicology</kwd>
              </kwd-group>
    </article-meta>
  </front>
</article>