Fighting cancer with translation inhibitors: a quantum mechanics view on the complex between the antitumor marine alkaloid agelastatin A and the yeast 80S ribosome.

The alkaloid agelastatin A (AGA) has raised great interest for its potent antitumor activity and intriguing molecular structure. This led to multifarious total syntheses and the antitumor activity was related to eukaryotic translation inhibition, unraveling the structure of the complex with the 80S yeast ribosome at atomic level. What remained unanswered is the relative weight of the various interactions, a hierarchy of great interest in planning improved antitumor agents in the AGA family. This has been investigated here along QM-MM in explicit water. What emerged was a high and constant HOMO-LUMO gap, speaking for a robust AGA-ribosome complex also in solution, within which AGA's relaxed twisting ability showed up markedly. It became also clear that AGA's ring A, despite its formal representation, has no pyrrole properties. Br-π and π-π stacking interactions and H-bonds with surrounding nucleotides, as from X-ray diffraction, are fully supported by MEP maps. But the main finding was that MD-driven dissection of the various contributions revealed a dominance of the entropically favored chelate H-bonding between AGA's central amide system and U2869. In contrast, the X-ray diffraction assignment of C5-OH H-bonding to U2873 is not supported. Along similar lines it was found that interactions of the ribosome with the structural analog CEAA, where chlorine and ethyl replace AGA's bromine and methyl, differ markedly, except as to the chelate bonding with U2869, which persists as a character of the class. This should be useful in the invention of improved translation inhibitors in the agelastatin class. [ABSTRACT FROM AUTHOR]