Issue 10, 2021

Analysis of physicochemical properties of protein–protein interaction modulators suggests stronger alignment with the “rule of five”

Abstract

Despite the important roles played by protein–protein interactions (PPIs) in disease, they have been long considered as ‘undruggable’. However, recent advances have suggested that PPIs are druggable but may not follow conventional rules of ‘drug ability’. Here we explore which physicochemical parameters are essential for a PPI modulator to be a clinical drug by analysing the physicochemical properties of small-molecule PPI modulators in the market, in clinical trials, and published. Our analysis reveals that those compounds currently on the market have a larger range of values for most of the physicochemical parameters, whereas those in clinical trials fit much more stringently to standard drug-like parameters. This observation was particularly true for molecular weight, clog P and topological polar surface area, where aside from a few outliers, most of the compounds in clinical trials fit within standard drug-like parameters. This implies that the newer PPI modulators are more drug-like than those currently on the market, suggesting that designing new PPI-specific screening libraries should remain within standard drug-like parameters in order to obtain a clinical candidate. Taken together, our analysis has important implications for designing future drug discovery campaigns aimed at targeting PPIs.

Graphical abstract: Analysis of physicochemical properties of protein–protein interaction modulators suggests stronger alignment with the “rule of five”

Supplementary files

Article information

Article type
Research Article
Submitted
25 जून 2021
Accepted
27 जुलाई 2021
First published
27 जुलाई 2021

RSC Med. Chem., 2021,12, 1731-1749

Analysis of physicochemical properties of protein–protein interaction modulators suggests stronger alignment with the “rule of five”

J. Truong, A. George and J. K. Holien, RSC Med. Chem., 2021, 12, 1731 DOI: 10.1039/D1MD00213A

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements