Computational design of small organic molecules as enzyme mimics: Spirocyclic organocatalysts with high-level structural and electrostatic preorganization for transesterification reactions

Natural enzymes are proficient catalysts. In the past few years, chemists have tried to mimic enzymes and synthesized amino-acid based catalysts to optimize efficiency of many different transformations. Recently, new transesterification catalysts were developed called "spiroligozymes", by placing the catalytic machinery of esterase enzymes onto modular spiro-fused bispeptides with the help of quantum mechanical transition state calculations using the "inside-out" approach. Molecular dynamics simulations showed that, in contrast to the observed behavior in naturally evolved enzymes, the catalytic groups in spiroligozymes sample numerous alternative conformations and the H-bond between the nucleophilic dyad essential for catalysis is not maintained. These computational results suggest that the activities of spiroligozymes can be significantly improved by providing a high-level preorganization of the catalytic functional groups. For this purpose, the structural modifications that eliminate non-reactive conformations of spiroligozymes and fix the active conformation of catalytic groups were identified. Medchem transformations were used to obtain spiroligozyme derivatives. Conformational library for each spirologozyme derivative was generated with the MMFF force field using lowmodeMD sampling procedure. The conformers of selected derivatives were evaluated by quantum mechanical calculations. Molecular dynamics (MD) simulations were performed to evaluate whether the designed catalytic contacts were maintained in a dynamic environment in the presence of explicit solvent molecules. This work constitutes an important step towards the computational design of organocatalysts with preorganized functional groups as well as reaching an enzyme-like activity with small organic molecules.