| 1. |
- Atilaw, Yoseph, et al.
(författare)
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Solution Conformations Shed Light on PROTAC Cell Permeability
- 2021
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Ingår i: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 12:1, s. 107-114
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Tidskriftsartikel (refereegranskat)abstract
- Proteolysis targeting chimeras (PROTACs) induce intracellular degradation of target proteins. Their bifunctional structure puts degraders in a chemical space where ADME properties often complicate drug discovery. Herein we provide the first structural insight into PROTAC cell permeability obtained by NMR studies of a VHL-based PROTAC (1), which is cell permeable despite having a high molecular weight and polarity and a large number of rotatable bonds. We found that 1 populates elongated and polar conformations in solutions that mimic extra- and intracellular compartments. Conformations were folded and had a smaller polar surface area in chloroform, mimicking a cell membrane interior. Formation of intramolecular and nonclassical hydrogen bonds, π–π interactions, and shielding of amide groups from solvent all facilitate cell permeability by minimization of size and polarity. We conclude that molecular chameleonicity appears to be of major importance for 1 to enter into target cells.
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| 2. |
- Poongavanam, Vasanthanathan, et al.
(författare)
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Linker-Dependent Folding Rationalizes PROTAC Cell Permeability br
- 2022
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Ingår i: Journal of Medicinal Chemistry. - : American Chemical Society (ACS). - 0022-2623 .- 1520-4804. ; 65:19, s. 13029-13040
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Tidskriftsartikel (refereegranskat)abstract
- Proteolysis-targeting chimeras (PROTACs) must be cell permeable to reach their target proteins. This is challenging as the bivalent structure of PROTACs puts them in chemical space at, or beyond, the outer limits of oral druggable space. We used NMR spectroscopy and molecular dynamics (MD) simulations independently to gain insights into the origin of the differences in cell permeability displayed by three flexible cereblon PROTACs having closely related structures. Both methods revealed that the propensity of the PROTACs to adopt folded conformations with a low solvent-accessible 3D polar surface area in an apolar environment is correlated to high cell permeability. The chemical nature and the flexibility of the linker were essential for the PROTACs to populate folded conformations stabilized by intramolecular hydrogen bonds, pi-pi interactions, and van der Waals interactions. We conclude that MD simulations may be used for the prospective ranking of cell permeability in the design of cereblon PROTACs.
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| 3. |
- Poongavanam, Vasanthanathan, et al.
(författare)
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Predictive Modeling of PROTAC Cell Permeability with Machine Learning
- 2023
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Ingår i: ACS Omega. - : American Chemical Society (ACS). - 2470-1343. ; 8:6, s. 5901-5916
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Tidskriftsartikel (refereegranskat)abstract
- Approaches for predicting proteolysis targeting chimera (PROTAC) cell permeability are of major interest to reduce resource-demanding synthesis and testing of low-permeable PROTACs. We report a comprehensive investigation of the scope and limitations of machine learning-based binary classification models developed using 17 simple descriptors for large and structurally diverse sets of cereblon (CRBN) and von Hippel-Lindau (VHL) PROTACs. For the VHL PROTAC set, kappa nearest neighbor and random forest models performed best and predicted the permeability of a blinded test set with >80% accuracy (k >= 0.57). Models retrained by combining the original training and the blinded test set performed equally well for a second blinded VHL set. However, models for CRBN PROTACs were less successful, mainly due to the imbalanced nature of the CRBN datasets. All descriptors contributed to the models, but size and lipophilicity were the most important. We conclude that properly trained machine learning models can be integrated as effective filters in the PROTAC design process.
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