Progress in epoxyhydrolase calculations, design, and synthesis of chiral heterocyclic compounds

Chiral heterocyclic compounds are widely used in synthetic chemistry, natural products, pharmaceuticals, pesticides and materials, among which chiral nitrogen/oxygen heterocyclic compounds are the core building blocks
of many biological and physiologically active molecules.
At present, the synthesis of chiral nitrogen/oxocyclic compounds mainly involves metal catalysis and organic small molecule catalysis, and in recent years, biocatalytic methods designed and modified by calculation have become a research hotspot
.

Sun Zhoutong, a researcher at the Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, and others calculated and designed the limonene epoxyhydrolase (LEH) substrate binding pocket active site, reconstructed its active center hydrogen bond network, broke the original ring-opening mechanism of water-dependent molecules on epoxy substrate, realized the Baldwin cyclization and desymmetry reaction of epoxy compounds, and synthesized a variety of chiral nitrogen/oxocyclic compounds, which can be used to construct a series of natural products and potential drug precursors
。 Through crystal structure elucidation and computational simulation, the molecular mechanism
by which the optimal mutant activity center can mediate intramolecular nucleophile cyclization of substrates and generate chiral heterocyclic compounds is revealed.
This study provides a new reference
for the design of similar enzymatic new reactions and the realization of biosynthesis of new molecules.

The results were published in
Nature Communications.
The relevant research work was supported
by the National Key R&D Program of China, the National Natural Science Foundation of China, the Tianjin Natural Science Foundation and the Tianjin Synthetic Biotechnology Innovation Capacity Improvement Action.

Schematic diagram of computational design epoxy hydrolase to achieve synthesis of chiral heterocyclic compounds