Our own bodies hold the key to designing safer drugs
Based on a study of 566 drugs that interact with 129 different proteins, researchers from the Systems Pharmacology research group, part of the Research Programme on Biomedical Informatics (GRIB) (IMIM-UPF) in collaboration with researchers from the University of New Mexico, in the United States, realised that 71% of drugs have stronger affinities for their target proteins than those of the small internal molecules responsible for regulating their functions. Surprisingly, this is the first time that the affinities of endogenous ligands and drugs for the same proteins have been quantified.
Humans have thousands of proteins, each with a specific function that is often regulated by thousands of small molecules synthesised by our bodies. This set of small molecules, also known as “endogenous metabolites”, is known as the “human metabolome”. Each one interacts with its native protein with a certain affinity that has been carefully optimised, in a natural way, throughout the long process of evolution, and this can vary between species and even in some instances, more subtly, between individuals.
Most pharmaceuticals are small synthetic molecules that exert their therapeutic action through optimal interaction with one or more proteins whose function is regulated by one of our small internal molecules.
“To date, no one had ever considered the idea that a drug’s minimum interaction with its target protein should be similar to the affinity shown by the body’s own small molecule. We have discovered that our own molecules, naturally optimised by evolution, provide the frame of reference necessary for efficiently designing more effective and safer drugs”, explain the researchers.
More than 90% of candidate drug molecules fail to pass the preclinical phase (tests using cells, tissues, and animals) or the clinical phase (tests on people) due to efficacy or toxicity problems, and this percentage has not dropped significantly over the last decade. “Incorporating the affinity of endogenous molecules for their native proteins as a reference threshold in the preclinical drug design phase would have an important impact on improving the efficiency of the optimisation process, reducing animal testing and the associated financial costs. It would also allow an initial estimate of the molecule’s safety margins, and potentially reduce the risk of the drug failing in the clinical phase due to translational problems between species”, conclude the resarchers.
The study was published in the prestigious journal Drug Discovery Today, which also dedicated the Editorial to it, and it has been reviewed by Nature Reviews Drug Discovery.
It’s the first time that the affinities of endogenous ligands and drugs for the same proteins have been quantified