A new study detects for the first time a direct relationship between the affinity of human endogenous metabolites for their native proteins and the minimum affinity that a drug targeting these proteins must have. More than 90% of drug candidate molecules fail to overcome the preclinical or clinical phase due to efficacy or toxicity problems.

In a study on 566 drugs that interact with 129 different proteins, scientists from the Systems Pharmacology group of the Biomedical Informatics Program (GRIB), a joint program of Hospital del Mar Institute for Medical Research (IMIM) and Pompeu Fabra University (UPF), observed that 71% of drugs have greater affinities with their more potent target proteins than with the small internal molecules responsible for regulating their functions.

This work, in collaboration with researchers from the University of New Mexico (USA) is a pioneer in establishing a quantitative relationship between the affinities of endogenous metabolites and drugs for the same proteins.

Humans have thousands of proteins, each with a specific function and often regulated by thousands of small molecules that our body is responsible for synthesizing.

The set of these small molecules, also called endogenous metabolites, is known as human metabolome. Each of them interacts with its native protein with a certain affinity that has been carefully optimized naturally during the long evolutionary process. This can vary between species and, more subtly, between individuals.

Most drugs are small synthetic molecules that exert their therapeutic action interacting precisely with one or more proteins which function is regulated by one of our small internal molecules.

The interaction of a drug with its target protein must have at least the affinity of the small molecule that we have in the body. We have discovered that, our own molecules, naturally optimized by evolution, establish the necessary frameworks to design more efficient and safe drugs more efficiently,” explains Jordi Mestres, GRIB coordinator.

Toxicity problems

More than 90% of drug candidate molecules fail to overcome the preclinical phase (tests in cells, tissues, and animals) or the clinical phase (tests in humans) due to efficacy or toxicity problems and this percentage has not been reduced significantly in the last decade.

Incorporating the affinity of the endogenous molecules for their native proteins –as a reference threshold during the preclinical phase of drug design– would have an important impact on improving the efficiency of the optimization process and reducing the tests in animals and associated economic costs, while allowing a first approximation of the safety margins of the molecule and reducing the risk of drug fall in the clinical phase due to translational problems between species,” concludes Jordi Mestres.

The study has been published in the journal Drug Discovery Today , and the Nature Reviews Drug Discovery has made a review on the article.


Source: SINC