American Chemical Society
jm2c01068_si_004.pdb (613.54 kB)

Paradoxical Increase of Permeability and Lipophilicity with the Increasing Topological Polar Surface Area within a Series of PRMT5 Inhibitors

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posted on 2022-09-07, 14:05 authored by Upendra Argikar, Markus Blatter, Dallas Bednarczyk, Zhuoliang Chen, Young Shin Cho, Michaël Doré, Jennifer L. Dumouchel, Samuel Ho, Klemens Hoegenauer, Toshio Kawanami, Simon Mathieu, Erik Meredith, Henrik Möbitz, Stephen K. Murphy, Saravanan Parthasarathy, Carole Pissot Soldermann, Jobette Santos, Serena Silver, Suzanne Skolnik, Aleksandar Stojanovic
An imidazolone → triazolone replacement addressed the limited passive permeability of a series of protein arginine methyl transferase 5 (PRMT5) inhibitors. This increase in passive permeability was unexpected given the increase in the hydrogen bond acceptor (HBA) count and topological polar surface area (TPSA), two descriptors that are typically inversely correlated with permeability. Quantum mechanics (QM) calculations revealed that this unusual effect was due to an electronically driven disconnect between TPSA and 3D-PSA, which manifests in a reduction in overall HBA strength as indicated by the HBA moment descriptor from COSMO-RS (conductor-like screening model for real solvation). HBA moment was subsequently deployed as a design parameter leading to the discovery of inhibitors with not only improved passive permeability but also reduced P-glycoprotein (P-gp) transport. Our case study suggests that hidden polarity as quantified by TPSA-3DPSA can be rationally designed through QM calculations.