Structure–Permeability Relationship of Semipeptidic Macrocycles—Understanding and Optimizing Passive Permeability and Efflux Ratio

Roux, Antoine Le; Blaise, Émilie; Boudreault, Pierre‐Luc; Comeau, Christian; Doucet, Annie; Giarrusso, Marilena A.; Collin, Marie‐Pierre; Neubauer, Thomas M.; Kölling, Florian; Göller, Andreas H.; Seep, Lea; Tshitenge, Dieudonné Tshitenge; Wittwer, Matthias; Kullmann, Maximilian; Hillisch, Alexander; Mittendorf, Joachim; Marsault, Éric

doi:10.1021/acs.jmedchem.0c00013

Cited by 25 publications

(44 citation statements)

References 49 publications

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“…15,16,52 The challenges posed by modelling of permeability for molecular chameleons also apply to flexible cyclic peptides, as reported previously by others. 10,14 We conclude that regression modelling of macrocycle cell permeability requires an analysis of the investigated dataset in terms of flexibility and its impact on the formation of intramolecular hydrogen bonds and other structural features masking polar regions, rather than a fast but a critical submission to computational tools.…”

Section: Discussionmentioning

confidence: 99%

“…8e13 These models have been developed using substantial computational and experimental resources and are based on either a low-dielectric 8 or a congruent 11 conformation as the permeating species. Alternatively, ensemble-based solvent accessible surface area 13 and ensemble-based 3D polar surface area 14 have been found to be good predictors of the permeability of cyclic peptides and semipeptidic macrocycles, respectively.…”

Section: Introductionmentioning

confidence: 99%

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Predicting the Permeability of Macrocycles from Conformational Sampling – Limitations of Molecular Flexibility

Poongavanam

Atilaw

et al. 2021

Journal of Pharmaceutical Sciences

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Macrocycles constitute superior ligands for targets that have flat binding sites but often require long synthetic routes, emphasizing the need for property prediction prior to synthesis. We have investigated the scope and limitations of machine learning classification models and of regression models for predicting the cell permeability of a set of de novo-designed, drug-like macrocycles. 2D-Based classification models, which are fast to calculate, discriminated between macrocycles that had low-medium and high permeability and may be used as virtual filters in early drug discovery projects. Importantly, stereo-and regioisomer were correctly classified. QSPR studies of two small sets of comparator drugs suggested that use of 3D descriptors, calculated from biologically relevant conformations, would allow development of more precise regression models for late phase drug projects. However, a 3D permeability model could only be developed for a rigid series of macrocycles. Comparison of NMR based conformational analysis with in silico conformational sampling indicated that this shortcoming originates from the inability of the molecular mechanics force field to identify the relevant conformations for flexible macrocycles. We speculate that a Kier flexibility index of 10 constitutes a current upper limit for reasonably accurate 3D prediction of macrocycle cell permeability.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Predicting the Permeability of Macrocycles from Conformational Sampling – Limitations of Molecular Flexibility

Poongavanam

Atilaw

et al. 2021

Journal of Pharmaceutical Sciences

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“… 13 − 15 However, prediction of biologically relevant conformations of complex macrocycles is far from trivial. 14 , 16 Some promising progress has been made for small sets of macrocyclic peptides, 5 , 17 , 18 and natural-product-inspired macrocycles, 14 , 19 , 20 albeit by using substantial time and computational resources for each compound. However, in order to impact on the prioritization of compounds for synthesis in lead optimization, medium- to high-throughput methods that are amenable to automation are desired.…”

mentioning

confidence: 99%

Cell Permeability of Isomeric Macrocycles: Predictions and NMR Studies

Begnini

Poongavanam

Atilaw

et al. 2021

ACS Med. Chem. Lett.

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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 moderately flexible macrocycles, thereby contributing to the prioritization of macrocycles for synthesis in lead optimization.

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“…This cyclization and scoring strategy is meanwhile routinely used in early discovery projects at Sanofi. Potential future advances in predicting permeability 140 and pharmacokinetic properties of macrocycles will further strengthen the applicability of the presented method for the multi-parameter optimization of macrocycles. Taken together this approach marks a large step forward in accelerated pharmaceutical design via efficient molecular cyclization.…”

Section: Discussionmentioning

confidence: 87%

Automated Design of Macrocycles for Therapeutic Applications: From Small Molecules to Peptides and Proteins

et al. 2020

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Macrocycles and cyclic peptides are increasingly attractive therapeutic modalities as they often have improved affinity, are able to bind to extended protein interfaces and otherwise have favorable properties. Macrocyclization of a known binder molecule has the potential to stabilize its bioactive conformation, improve its metabolic stability, cell permeability and in certain cases oral bioavailability. Herein, we present an in silico approach that automatically generates, evaluates and proposes cyclizations utilizing a library of well-established chemical reactions and reagents. Using the three-dimensional (3D) conformation of the linear molecule in complex with a target protein as starting point, this approach identifies attachment points, generates linkers, evaluates the conformational landscape of suitable linkers and their geometric compatibility and ranks the resulting molecules with respect to their predicted conformational stability and interactions with the target protein. As we show here with several prospective and retrospective case studies, this procedure can be applied for the macrocyclization of small molecules and peptides and even PROTACs and proteins.The presented approach is an important step towards the enhanced utilization of macrocycles andcyclic peptides as attractive therapeutic modalities. File list (2) download file view on ChemRxiv DesignOfMacrocycles_chemrxiv.pdf (1.85 MiB) download file view on ChemRxiv SUPPORTING INFORMATION.pdf (458.87 KiB)

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Structure–Permeability Relationship of Semipeptidic Macrocycles—Understanding and Optimizing Passive Permeability and Efflux Ratio

Cited by 25 publications

References 49 publications

Predicting the Permeability of Macrocycles from Conformational Sampling – Limitations of Molecular Flexibility

Predicting the Permeability of Macrocycles from Conformational Sampling – Limitations of Molecular Flexibility

Cell Permeability of Isomeric Macrocycles: Predictions and NMR Studies

Automated Design of Macrocycles for Therapeutic Applications: From Small Molecules to Peptides and Proteins

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