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The development of novel molecules targeting the <jats:inline-formula><jats:alternatives><jats:tex-math>$$\\mu$$<\/jats:tex-math><mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\">\n                  <mml:mi>\u03bc<\/mml:mi>\n                <\/mml:math><\/jats:alternatives><\/jats:inline-formula>-opioid receptor (MOR) in inflamed, but not in healthy tissue, could significantly reduce these unwanted effects. Finding such novel molecules can be achieved by <jats:italic>maximizing<\/jats:italic> the binding affinity to the MOR at acidic pH while <jats:italic>minimizing<\/jats:italic> it at neutral pH, thus combining two conflicting objectives. Here, this <jats:italic>multi-objective optimal affinity approach<\/jats:italic> is presented, together with a virtual drug discovery pipeline for its practical implementation. When applied to finding pH-specific drug candidates, it combines protonation state-dependent structure and ligand preparation with high-throughput virtual screening. We employ this pipeline to characterize a set of MOR agonists identifying a morphine-like opioid derivative with higher predicted binding affinities to the MOR at low pH compared to neutral pH. Our results also confirm existing experimental evidence that NFEPP, a previously described fentanyl derivative with reduced side effects, and recently reported <jats:inline-formula><jats:alternatives><jats:tex-math>$$\\beta$$<\/jats:tex-math><mml:math xmlns:mml=\"http:\/\/www.w3.org\/1998\/Math\/MathML\">\n                  <mml:mi>\u03b2<\/mml:mi>\n                <\/mml:math><\/jats:alternatives><\/jats:inline-formula>-fluorofentanyls and -morphines show an increased specificity for the MOR at acidic pH when compared to fentanyl and morphine. We further applied our approach to screen a &gt;50K ligand library identifying novel molecules with pH-specific predicted binding affinities to the MOR. The presented differential docking pipeline can be applied to perform multi-objective affinity optimization to identify safer and more specific drug candidates at large scale.<\/jats:p>","DOI":"10.1186\/s13321-023-00746-4","type":"journal-article","created":{"date-parts":[[2023,9,19]],"date-time":"2023-09-19T12:02:01Z","timestamp":1695124921000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Novel multi-objective affinity approach allows to identify pH-specific \u03bc-opioid receptor agonists"],"prefix":"10.1186","volume":"15","author":[{"given":"Christopher","family":"Secker","sequence":"first","affiliation":[]},{"given":"Konstantin","family":"Fackeldey","sequence":"additional","affiliation":[]},{"given":"Marcus","family":"Weber","sequence":"additional","affiliation":[]},{"given":"Sourav","family":"Ray","sequence":"additional","affiliation":[]},{"given":"Christoph","family":"Gorgulla","sequence":"additional","affiliation":[]},{"given":"Christof","family":"Sch\u00fctte","sequence":"additional","affiliation":[]}],"member":"297","published-online":{"date-parts":[[2023,9,19]]},"reference":[{"issue":"2","key":"746_CR1","first-page":"61","volume":"27","author":"R Schmitz","year":"1985","unstructured":"Schmitz R (1985) Friedrich Wilhelm Serturner and the discovery of morphine. 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