Study into the cyclization of an epoxy-alcohol to the energetically disfavored product by peptides from non-biased combinatorial libraries

Catalysis of a reaction to products via an energetically disfavored pathway to be performed by small molecules is not documented to date. To question that, we chose to study the possible cyclization of an epoxy–alcohol to the product interdicted by Baldwin’s rules. For achieving this goal, thousands of randomly chosen peptidic combinatorial library members were screened against a transition state analog of the disfavored reaction. This method led to the discovery of several sequences which could behave as catalysts of the reaction. Complexes between the epoxy–alcohol and certain peptides were studied using molecular modeling to shed light on the binding and mode of action of these peptides and the reason they were selectively chosen. Certain re-synthesized peptides amounted to a 10–15 fold increase in the production of the disfavored product when added to the reaction.