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

Inhibition of respiratory system complex I (CI) has become an encouraging anti-cancer strategy, encouraging the look and using inhibitors, whose mechanism of action, effectiveness and specificity remain elusive. As CI is really a central player of cellular bioenergetics, a finely tuned dosing of targeting drugs is needed to prevent negative effects. We compared the specificity and mode of action of CI inhibitors metformin, BAY 87-2243 and EVP 4593 using cancer cell models lacking of CI. Ideas reveal that both BAY 87-2243 and EVP 4593 were selective, as the antiproliferative results of metformin were significantly independent from CI inhibition. Molecular docking predictions established that our prime efficiency of BAY 87-2243 and EVP 4593 may be a consequence of the tight network of bonds within the quinone binding pocket, although in various sites. The majority of the proteins involved with such interactions are conserved across species and just rarely found mutated in human. Our data create a situation for caution when talking about metformin like a CI-targeting compound, and highlight the requirement for dosage optimization and careful look EVP4593 at molecular interactions between inhibitors and also the holoenzyme.