| 1. |
- Begnini, Fabio, et al.
(författare)
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Importance of Binding Site Hydration and Flexibility Revealed When Optimizing a Macrocyclic Inhibitor of the Keap1-Nrf2 Protein-Protein Interaction
- 2022
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 65:4, s. 3473-3517
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Tidskriftsartikel (refereegranskat)abstract
- Upregulation of the transcription factor Nrf2 by inhibition of the interaction with its negative regulator Keap1 constitutes an opportunity for the treatment of disease caused by oxidative stress. We report a structurally unique series of nanomolar Keap1 inhibitors obtained from a natural product-derived macrocyclic lead. Initial exploration of the structure-derived macrocyclic lead. Initial exploration of the structure-activity relationship of the lead, followed by structure-guided optimization, resulted in a 100-fold improvement in inhibitory potency. The macrocyclic core of the nanomolar inhibitors positions three pharmacophore units for productive interactions with key residues of Keap1, including R415, R483, and Y572. Ligand optimization resulted in the displacement of a coordinated water molecule from the Keap1 binding site and a significantly altered thermodynamic profile. In addition, minor reorganizations of R415 and R483 were accompanied by major differences in affinity between ligands. This study therefore indicates the importance of accounting both for the hydration and flexibility of the Keap1 binding site when designing high-affinity ligands.
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| 2. |
- Begnini, Fabio, et al.
(författare)
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Mining Natural Products for Macrocycles to Drug Difficult Targets
- 2021
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 64:2, s. 1054-1072
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Tidskriftsartikel (refereegranskat)abstract
- Lead generation for difficult-to-drug targets that have large, featureless, and highly lipophilic or highly polar and/or flexible binding sites is highly challenging. Here, we describe how cores of macrocyclic natural products can serve as a high-quality in silico screening library that provides leads for difficult-to-drug targets. Two iterative rounds of docking of a carefully selected set of natural-product-derived cores led to the discovery of an uncharged macrocyclic inhibitor of the Keap1-Nrf2 protein- protein interaction, a particularly challenging target due to its highly polar binding site. The inhibitor displays cellular efficacy and is well-positioned for further optimization based on the structure of its complex with Keapl and synthetic access. We believe that our work will spur interest in using macrocyclic cores for in silico-based lead generation and also inspire the design of future macrocycle screening collections.
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| 3. |
- Begnini, Fabio, et al.
(författare)
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Structure-based optimization of a macrocyclic inhibitor of the Keap1-Nrf2 protein-protein interaction
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Activation of the transcription factor Nrf2 by inhibition of the interaction with its negative regulator Keap1 constitutes a potential opportunity for the treatment of oxidative stress related disease. Although highly potent inhibitors of the Keap1–Nrf2 protein-protein interaction (PPI) have been reported, these compounds are based on a few reoccurring scaffolds. Here, we report a novel, structurally unique series of double-digit nM Keap1 inhibitors obtained by optimization of a natural product-derived macrocyclic lead. Exploration of the structure-activity relationship, followed by structure-based design led to a 100-fold improvement in inhibitory potency compared to the starting point. The macrocyclic core positions the pharmacophores of the inhibitors suitably for productive interactions with key residues of Keap1, including R415 and R483; both of which contribute to the highly polar nature of the binding site for Nrf2. In addition, we discovered that minor, ligand-induced reorganizations of these two arginine residues are accompanied by major differences in binding affinity between compounds in the series.
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| 4. |
- Begnini, Fabio, et al.
(författare)
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Cell Permeability of Isomeric Macrocycles : Predictions and NMR Studies
- 2021
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Ingår i: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 12:6, s. 983-990
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Tidskriftsartikel (refereegranskat)abstract
- Conformation-dependent 3D descriptors have been shown to provide better predictions of the physicochemical properties of macrocycles than 2D descriptors. However, the computational identification of relevant conformations for macrocycles is nontrivial. Herein, we report that the Caco- 2 cell permeability difference between a pair of diastereomeric macrocycles correlated with their solvent accessible 3D polar surface area and radius of gyration. The descriptors were calculated from the macrocycles’ solution- phase conformational ensembles and independently from ensembles obtained by conformational sampling. Calculation of the two descriptors for three other stereo- and regioisomeric macrocycles also allowed the correct ranking of their cell permeability. Methods for conformational sampling may thus allow ranking of passive permeability for moderatelyflexible macrocycles, thereby contributing to the prioritization of macro- cycles for synthesis in lead optimization.
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| 5. |
- Tyagi, Mohit, et al.
(författare)
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Toward the Design of Molecular Chameleons : Flexible Shielding of an Amide Bond Enhances Macrocycle Cell Permeability
- 2018
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Ingår i: Organic Letters. - : AMER CHEMICAL SOC. - 1523-7060 .- 1523-7052. ; 20:18, s. 5737-5742
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Tidskriftsartikel (refereegranskat)abstract
- A series of macrocycles inspired by natural products were synthesized to investigate how side-chains may shield amide bonds and influence cell permeability. NMR spectroscopy and X-ray crystallography revealed that the phenyl group of phenylalanine, but not the side-chains of homologous or aliphatic amino acids, shields the adjacent amide bond through an intramolecular NH-pi interaction. This resulted in increased cell permeability, suggesting that NH-pi interactions may be used in the design of molecular chameleons.
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