UC Santa Barbara chemistry professor Yang Yang and collaborators have developed an enzymatic multicomponent reaction that produces six distinct molecular scaffolds many of which were previously inaccessible by conventional chemical or biological methods.

The ability to generate novelty and molecular diversity is particularly important to medicinal chemistry,” Yang said. “Biocatalysis was long viewed mainly as a tool for large-scale production of specialty chemicals, but our work shows that new biocatalytic methods can also accelerate discovery chemistry by enabling combinatorial synthesis of novel molecules.

The research, published in Science and supported by the NIH and NSF, advances the field of diversity-oriented synthesis an approach that builds structurally diverse molecular libraries for screening. Unlike traditional target-focused synthesis, this strategy increases the chances of finding bioactive compounds by exploring a broader chemical space. At the core of this work is carbon -carbon bond formation, the fundamental linkage in organic molecules, including proteins and DNA.

Yang’s team, in collaboration with Peng Liu at the University of Pittsburgh, devised a cooperative process that combines enzymes with light-harvesting photocatalysts to generate novel scaffolds with rich stereochemistry. Enzymes, nature’s highly selective catalysts, are powerful but limited to certain substrates, while synthetic catalysts offer versatility but lack precision. By merging both, the researchers achieved six new products via carbon–carbon bond formation with exceptional control.

Through enzyme photocatalyst cooperativity using a radical mechanism, we developed multicomponent biocatalytic reactions previously unknown to chemistry and biology, Yang explained. These enzymes proved surprisingly general, functioning across diverse substrates, enabling one of the most complex multicomponent enzymatic reactions our lab has developed.

The study involved contributions from Chen Zhang, Jun Zhou, and Silvia M. Rivera (UCSB), Pei-Pei Xie and Turki M. Alturaifi (University of Pittsburgh), and James Finnegan and Simon Charnock (Prozimix Ltd., UK).

Source: https://news.ucsb.edu/2025/022011/new-catalysis-method-can-generate-library-novel-molecules-drug-discovery