NDUFS3 knockout cancer cells and molecular docking reveal specificity and mode of action of anti-cancer respiratory complex I inhibitors

Inhibition of respiratory complex I (CI) is becoming a promising anti-cancer strategy, encouraging the design and the use of inhibitors, whose mechanism of action, efficacy and specificity remain elusive. As CI is a central player of cellular bioenergetics, a finely tuned dosing of targeting drugs is required to avoid side effects. We compared the specificity and mode of action of CI inhibitors metformin, BAY 87-2243 and EVP 4593 using cancer cell models devoid of CI. Here we show that both BAY 87-2243 and EVP 4593 were selective, while the antiproliferative effects of metformin were considerably independent from CI inhibition. Molecular docking predictions indicated that the high efficiency of BAY 87-2243 and EVP 4593 may derive from the tight network of bonds in the quinone binding pocket, although in different sites. Most of the amino acids involved in such interactions are conserved across species and only rarely found mutated in human. Our data make a case for caution when referring to metformin as a CI-targeting compound, and highlight the need for dosage optimization and careful evaluation of molecular interactions between inhibitors and the holoenzyme.

 

Comments：

The inhibition of respiratory complex I (CI) has emerged as a promising anti-cancer strategy, and researchers have been designing and using inhibitors to target this complex. However, the efficacy, specificity, and mechanism of action of these inhibitors are not well understood, and careful dosing is required to avoid side effects because CI plays a central role in cellular bioenergetics. To compare the specificity and mode of action of CI inhibitors metformin, BAY 87-2243, and EVP 4593, researchers used cancer cell models devoid of CI.

The study found that both BAY 87-2243 and EVP 4593 were selective in their inhibition of CI, while the antiproliferative effects of metformin were considerably independent of CI inhibition. Molecular docking predictions suggested that the high efficiency of BAY 87-2243 and EVP 4593 may be due to the tight network of bonds in the quinone binding pocket, although in different sites. Most of the amino acids involved in these interactions are conserved across species and rarely found mutated in humans.

These findings suggest that caution is needed when referring to metformin as a CI-targeting compound, and that careful dosage optimization and evaluation of molecular interactions between inhibitors and the holoenzyme are necessary. Overall, this study highlights the need for further research to better understand the mechanism of action and specificity of CI inhibitors, as well as their potential side effects.

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