{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,24]],"date-time":"2026-09-24T12:03:40Z","timestamp":1790251420516,"version":"4.1.0"},"reference-count":72,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T00:00:00Z","timestamp":1761782400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Medicinal Research Reviews"],"published-print":{"date-parts":[[2026,3]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>The active sites of numerous metalloproteins feature two metal ion cofactors\u2014either identical or distinct\u2014that are positioned in close proximity, typically around 3.8\u2009\u00c5 apart. This two\u2010metal\u2010ion catalytic mechanism (TCM) endows these enzymes with a remarkable catalytic efficiency. Enzymes employing TCM play vital biological roles in both humans and pathogenic organisms, with some identified as validated therapeutic targets. Various rational drug design approaches, including nucleoside analogs, prodrugs, metal\u2010binding group design, bioisosteres, pharmacophore modeling, scaffold hopping, tautomerism, and structure\u2010based drug design, have been successfully applied to several enzymes with TCMs, thus yielding the development and approval of many small\u2010molecule drugs for the treatment of several diseases, including certain catastrophic illnesses, such as hepatitis C infection, coronavirus disease 2019, and acquired immune deficiency syndrome. Additionally, drug repurposing has proven to be a critical strategy in the development of therapeutics targeting TCM enzymes. This article reviews the significant achievements in design and development of small\u2010molecule drugs targeting several enzymes with TCMs, including RNA\u2010dependent RNA polymerase, HIV\u20101 integrase, influenza virus cap\u2010dependent endonuclease, and phosphodiesterase, hoping to offer valuable insights and guidance to facilitate future drug discovery efforts focused on these enzymes and related molecular targets.<\/jats:p>","DOI":"10.1002\/med.70023","type":"journal-article","created":{"date-parts":[[2025,10,30]],"date-time":"2025-10-30T08:25:39Z","timestamp":1761812739000},"page":"542-556","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Design and Development of Small\u2010Molecule Drugs Targeting Enzymes Utilizing Two\u2010Metal\u2010Ion Catalytic 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