Regensburg 2019 – wissenschaftliches Programm

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CPP: Fachverband Chemische Physik und Polymerphysik

CPP 13: Membranes and Vesicles II (joint session BP/CPP)

CPP 13.2: Vortrag

Montag, 1. April 2019, 15:15–15:30, H10

Drug-membrane permeability across chemical space — •Roberto Menichetti, Kiran H. Kanekal, and Tristan Bereau — Max Planck Institute for Polymer Research, Mainz, Germany

Unraveling the link between the chemical structure of a small drug-like molecule and its rate of passive permeation across a lipid membrane is of fundamental importance for pharmaceutical application. However, the elucidation of a structure-permeability relationship in terms of few molecular descriptors has been so far hampered by the overwhelming number of possible compounds. In this work, we reduce a priori the size of chemical space by relying on physics-based coarse-grained models, and perform high-throughput coarse-grained simulations (HTCG) to cover a subset of chemical space both efficiently and broadly. This comprehensive exploration allows us to derive a smooth surface relating the permeability of a compound to two simple molecular properties—the bulk partitioning free energy and acid dissociation constant. By projecting HTCG predictions back to atomistic resolution, we provide an estimate of the permeability coefficient for more than 500,000 small molecules in the range 30−160 Da. Our large scale analysis establishes a clear connection between specific functional groups and the resulting permeability, enabling for the first time inverse molecular design. This study further highlights that favoring the incorporation of certain groups will reduce the range of accessible permeabilities, thus affecting bioavailability.

[1] R. Menichetti, K. H. Kanekal, and T. Bereau, arXiv preprint
arXiv:1805.10158 (2018).