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1.	Begnini, Fabio, et al. (författare) Cell Permeability of Isomeric Macrocycles : Predictions and NMR Studies 2021 Ingår i: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 12:6, s. 983-990 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.

Begnini, Fabio, et al. (författare)
Cell Permeability of Isomeric Macrocycles : Predictions and NMR Studies
2021
Ingår i: ACS Medicinal Chemistry Letters. - : American Chemical Society (ACS). - 1948-5875. ; 12:6, s. 983-990
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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