Computational identification of novel organocatalytic structures as enzyme mimics

Spirocyclic oligomers formed by coupling chiral building blocks carrying the catalytic machinery of hydrolases (spiroligozymes) catalyze the transesterification of vinyl trifluoromethylacetate with methanol but suffer from the lack of enzyme-like preorganization of their catalytic functionalities in a well-defined geometry via H-bond networks. In this thesis, a computational protocol that combines different levels of theories to rapidly explore structural modifications for an improved structural preorganization was applied to a bifunctional parent spiroligozyme containing a pyridine-alcohol dyad that mimics the Ser-His-Asp/Glu catalytic triad of hydrolases. Calculations predict that a modification as simple as replacing the five-membered building block holding the alcohol moiety with a six-membered analog in the parent spiroligozyme significantly increases the occupancy of the H-bond between the benzyl alcohol-pyridine nucleophilic dyad. The computed energy profile is indicative of faster acylation of this derivative compared to the parent spiroligozyme and highlights the importance of inclusion of an oxyanion hole motif for efficient catalysis. With the aim of identifying new organocatalyst candidates containing both a nucleophilic dyad (amine-alcohol) and an oxyanion hole motif (urea/thiourea), a computational approach that combines quantum mechanical calculations with drug design tools was used. A pharmacophore query was generated based on a quantum mechanically optimized transition state model including amine-alcohol-urea catalytic motifs and was screened in the ZINC database. The search identified trifunctional hits in the required three-dimensional constellations. The work presented herein constitutes an important step toward the design of multifunctional organocatalysts with high catalytic efficiency.