Computational analysis of calculated physicochemical and ADMET properties of protein-protein interaction inhibitors

TLDR

PPI inhibitors are valuable but often exhibit poor ADMET properties, and prior in silico studies have mainly examined physicochemical traits, leaving other ADMET parameters underexplored. The study aimed to generate new insights into the ADMET profiles of iPPIs by performing computational analyses on eight diverse datasets. The datasets comprised compounds targeting enzymes, GPCRs, ion channels, nuclear receptors, allosteric modulators, oral marketed drugs, oral natural product‑derived drugs, and iPPIs, sourced from multiple databases. The analyses revealed several ADMET trends that can inform the design and optimization of future PPI inhibitors for drug discovery and chemical biology.

Abstract

Abstract The modulation of PPIs by low molecular weight chemical compounds, particularly by orally bioavailable molecules, would be very valuable in numerous disease indications. However, it is known that PPI inhibitors (iPPIs) tend to have properties that are linked to poor Absorption, Distribution, Metabolism, Excretion and Toxicity (ADMET) and in some cases to poor clinical outcomes. Previously reported in silico analyses of iPPIs have essentially focused on physicochemical properties but several other ADMET parameters would be important to assess. In order to gain new insights into the ADMET properties of iPPIs, computations were carried out on eight datasets collected from several databases. These datasets involve compounds targeting enzymes, GPCRs, ion channels, nuclear receptors, allosteric modulators, oral marketed drugs, oral natural product-derived marketed drugs and iPPIs. Several trends are reported that should assist the design and optimization of future PPI inhibitors, either for drug discovery endeavors or for chemical biology projects.