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Novel multi-objective affinity approach allows to identify pH-specific µ-opioid receptor agonists.
Secker, Christopher; Fackeldey, Konstantin; Weber, Marcus; Ray, Sourav; Gorgulla, Christoph; Schütte, Christof.
Afiliação
  • Secker C; Zuse Institute Berlin, Berlin, Germany. secker@zib.de.
  • Fackeldey K; Max Delbrück Center for Molecular Medicine, Berlin, Germany. secker@zib.de.
  • Weber M; Zuse Institute Berlin, Berlin, Germany.
  • Ray S; Institute of Mathematics, Technical University Berlin, Berlin, Germany.
  • Gorgulla C; Zuse Institute Berlin, Berlin, Germany.
  • Schütte C; Zuse Institute Berlin, Berlin, Germany.
J Cheminform ; 15(1): 85, 2023 Sep 19.
Article em En | MEDLINE | ID: mdl-37726792
Opioids are essential pharmaceuticals due to their analgesic properties, however, lethal side effects, addiction, and opioid tolerance are extremely challenging. The development of novel molecules targeting the [Formula: see text]-opioid receptor (MOR) in inflamed, but not in healthy tissue, could significantly reduce these unwanted effects. Finding such novel molecules can be achieved by maximizing the binding affinity to the MOR at acidic pH while minimizing it at neutral pH, thus combining two conflicting objectives. Here, this multi-objective optimal affinity approach 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 [Formula: see text]-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 >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.

Texto completo: 1 Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2023 Tipo de documento: Article