Related Experiment Video
Updated: Aug 29, 2025

Fluorescence-Based Measurements of Phosphatidylserine/Phosphatidylinositol 4-Phosphate Exchange Between Membranes
Published on: March 14, 2021
Paradoxical Increase of Permeability and Lipophilicity with the Increasing Topological Polar Surface Area within a
Upendra Argikar1, Markus Blatter2, Dallas Bednarczyk1
1Novartis Institutes for BioMedical Research, Cambridge, Massachusetts 02139, United States.
Abstract:
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.
Related Concept Videos
Carrier-Mediated Transport
Active transport involves two types of membrane-spanning transporters: uptake and efflux. Uptake transporters are expressed in the small...
Pore Transport and Ion-Pair Transport
Pore transport, also known as convective transport, is a process where small molecules like urea, water, and sugars rapidly cross cell membranes as though there were channels or pores in the membrane. Although direct microscopic evidence is limited but the concept of pores or channels is widely accepted based on physiological evidence. Despite the lack of direct...
Factors Affecting Dissolution: Drug Permeability, Stability and Stereochemistry
Membrane Fluidity
Mosaic nature of the membrane
The mosaic characteristic of the membrane helps the plasma membrane remain fluid. The integral proteins and lipids exist as separate but loosely-attached molecules in the membrane. The membrane is...
Factors Affecting Dissolution: Drug pKa, Lipophilicity and GI pH
A drug's pKa and the pH of the gastrointestinal (GI) tract play crucial roles...
Drug Absorption Mechanism: Passive Membrane Transport

