Structural Bases for the Synergistic Inhibition of Human Thymidylate Synthase and Ovarian Cancer Cell Growth by Drug Combinations

Combining drugs represent an approach to efficiently prevent and overcome drug resistance reduce toxicity; yet it is a highly challenging task, particularly if combinations of inhibitors the same enzyme target are considered. To show that crystallographic inhibition kinetic information can provide indicators cancer cell growth by two anti-human thymidylate synthase (hTS) drugs, we obtained X-ray crystal structure hTS:raltitrexed:5-fluorodeoxyuridine monophosphate (FdUMP) complex. Its analysis showed ternary complex with both molecules strongly bound inside catalytic cavity. The synergistic hTS its mechanistic rationale were consistent structural analysis. When administered in combination A2780 A2780/CP ovarian cells, inhibited additively/synergistically. Together, these results support idea crystallography for designing (or any other target)-directed accelerate preclinical research therapeutic application.