A New Drug Discovery Approach Based on Thermal Proteome Profiling to Develop More Effective Drugs

Abstract

: The search for disease-related targets and studying drug-protein and protein-protein interactions are central issues that would accelerate the clinical approval of a drug. Also, by developing an accurate method in this regard, time and resource consumption will significantly decrease. The low efficiency of some drugs in humans is a grave issue leading to a low rate of FDA approval after spending billions of dollars and decades of research. Several strategies and methods have been expanded to fill this gap, such as drug affinity responsive target stability (DARTS), stability of proteins from rates of oxidation (SPROX), cellular thermal shift assay (CETSA), and finally, thermal proteome profiling (TPP). The TPP is based on the combination of CETSA and quantitative mass spectrometry. Among recently introduced proteomics technologies, TPP demonstrates the ability to offer detailed proteomic profiles for the large-scale analysis of protein-ligand interactions, including endogenous ligands and proteins like cofactors and metabolites. TPP facilitates the identification of the markers governing drug efficacy and toxicity and provides an unbiased measure for estimating the rate of drug-target engagement. At a glance at TPP steps, after protein extraction, the molecule is exposed to different temperatures and drug concentrations. After discarding solubilized and stabilized proteins, the protein’s identity is investigated by mass spectrometry analysis. As a result of the protein’s structural stabilization after binding to its substrate, TTP helps to accurately identify target proteins with high throughput. In this study, we aimed to introduce the basics of this method and review most recent studies on this technique.