Metformin, the first drug chosen to be tested in a clinical trial aimed to target the biology of aging per se, has been clinically exploited for decades in the absence of a complete understanding of its therapeutic targets or chemical determinants.

Now, with the participation of Mind the Byte, Javier Menéndez led a team of scientists at the ICO and IDIBGI to outline a systematic chemoinformatics approach to computationally predict biomolecular targets of metformin. The results were published recently at the journal Aging Cell, an official journal of the Anatomical Society.

Using several of Mind the Byte’s structure- and ligand-based software tools and reference databases containing 1,300,000 chemical compounds and more than 9,000 binding-sites protein cavities, we identified 41 putative metformin targets including several epigenetic modifiers such as KDM6A/UTX.

In this regard, in vitro assays successfully confirmed the ability of metformin to inhibit the demethylation activity of purified KDM6A/UTX enzyme. Further structural studies revealed that metformin might occupy the same set of residues of the catalytic pocket of the enzyme. Finally, these results were supported by in vivo studies performed with pharmacological doses of metformin in drinking water and intraperitoneal injection in mice.

In summary, our biocomputational approach coupled to experimental validation reveals that metformin might directly regulate the biological machinery of aging by targeting core chromatin-modifiers of the epigenome.

Therefore, this study can provide a valuable insight to metformin clinical trials and might pave the way for the development of new healthspan-promoting treatments aimed to promote reduction of age-associated multimorbidity.

Original article: Metformin directly targets the H3K27me3 demethylase KDM6A/UTX. Cuyàs E, Verdura S, Llorach-Pares L, Fernández-Arroyo S, Luciano-Mateo F, Cabré N, Stursa J, Werner L, Martin-Castillo B, Viollet B, Neuzil J, Joven J, Nonell-Canals A, Sanchez-Martinez M, Menendez JA. Aging Cell. 2018 May 8:e12772. doi: 10.1111/acel.12772.