Structural Characterization of KOR Inactive and Active States for 3D Pharmacology and Drug Discovery

Zaidi, Saheem A.; Katritch, Vsevolod

doi:10.1007/164_2021_461

Cited by 2 publications

(1 citation statement)

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“…More recently, another structure of inactivestate KOR was solved with JDTic in complex with a Nb6 antibody (PDB-ID: 6VI4 [48]). The structure elucidation of the KOR and continued development of computational tools provide novel opportunities for computational modeling studies of receptor dynamics and for structure-based ligand discovery [49].…”

Section: Introductionmentioning

confidence: 99%

In Vitro, In Vivo and In Silico Characterization of a Novel Kappa-Opioid Receptor Antagonist

et al. 2022

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Kappa-opioid receptor (KOR) antagonists are promising innovative therapeutics for the treatment of the central nervous system (CNS) disorders. The new scaffold opioid ligand, Compound A, was originally found as a mu-opioid receptor (MOR) antagonist but its binding/selectivity and activation profile at the KOR and delta-opioid receptor (DOR) remain elusive. In this study, we present an in vitro, in vivo and in silico characterization of Compound A by revealing this ligand as a KOR antagonist in vitro and in vivo. In the radioligand competitive binding assay, Compound A bound at the human KOR, albeit with moderate affinity, but with increased affinity than to the human MOR and without specific binding at the human DOR, thus displaying a preferential KOR selectivity profile. Following subcutaneous administration in mice, Compound A effectively reverse the antinociceptive effects of the prototypical KOR agonist, U50,488. In silico investigations were carried out to assess the structural determinants responsible for opioid receptor subtype selectivity of Compound A. Molecular docking, molecular dynamics simulations and dynamic pharmacophore (dynophore) generation revealed differences in the stabilization of the chlorophenyl moiety of Compound A within the opioid receptor binding pockets, rationalizing the experimentally determined binding affinity values. This new chemotype bears the potential for favorable ADMET properties and holds promise for chemical optimization toward the development of potential therapeutics.

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Section: Introductionmentioning

confidence: 99%

In Vitro, In Vivo and In Silico Characterization of a Novel Kappa-Opioid Receptor Antagonist

et al. 2022

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Design of κ-Opioid Receptor Agonists for the Development of Potential Treatments of Pain with Reduced Side Effects

Santino

Gentilucci

2023

Molecules

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The κ-opioid receptor (KOR) has recently emerged as an alternative therapeutic target for the development of pain medications, without deleterious side effects associated with the μ-opioid receptor (MOR). However, modulation of KOR is currently under investigation for the treatment of depression, mood disorders, psychiatric comorbidity, and specific drug addictions. However, KOR agonists also trigger adverse effects including sedation, dysphoria, and hallucinations. In this respect, there is currently much debate on alternative paradigms. Recent effort has been devoted in search of biased ligands capable of selectively activating favorable signaling over signaling associated with unwanted side effects. On the other hand, the use of partial agonists is expected to allow the analgesia to be produced at dosages lower than those required to produce the adverse effects. More empirically, the unwanted central effects can be also avoided by using peripherally restricted agonists. In this review, we discuss the more recent trends in the design of KOR-selective, biased or partial, and finally, peripherally acting agonists. Special emphasis is given on the discussion of the most recent approaches for controlling functional selectivity of KOR-specific ligands.

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Structural Characterization of KOR Inactive and Active States for 3D Pharmacology and Drug Discovery

Cited by 2 publications

References 74 publications

In Vitro, In Vivo and In Silico Characterization of a Novel Kappa-Opioid Receptor Antagonist

In Vitro, In Vivo and In Silico Characterization of a Novel Kappa-Opioid Receptor Antagonist

Design of κ-Opioid Receptor Agonists for the Development of Potential Treatments of Pain with Reduced Side Effects

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