Olaf Wiest, Grace-Rupley Professor of Chemistry & Biochemistry, is the recipient of a 2025 University of Notre Dame Research Achievement Award. This prestigious award recognizes faculty for outstanding research accomplishments and for promoting graduate education. Wiest is a distinguished computational and experimental organic chemist, studying chemical reactivity and mechanisms with applications in molecular biophysics and drug design, particularly for the understanding and treatment of rare and neglected diseases. He is also the founder and lead principal investigator of the National Science Foundation Center for Computer-Assisted Synthesis (C-CAS).

Wiest’s research, resulting in over 200 peer-reviewed publications, focuses on developing a detailed understanding of how molecules interact with one another to advance synthetic methods and design new pharmaceutical therapeutics. One key area of study is the development of epigenetic modulators, which are compounds that regulate gene expression without changing DNA. With collaborators at Notre Dame and Cornell Medical College, Wiest discovered a library of epigenetic modulators targeting histone deacetylases that effectively decrease accumulated cholesterol, a main pathway of Niemann-Pick type C disease. These compounds were among the first to be tested in clinical trials to treat the disease. Another area of his work is on bromodomains, as they are critical targets implicated in the regulation of diseases including aggressive human squamous carcinoma. Wiest’s work helped to show that carefully designed molecules can competitively bind and prevent the work of these domains, slowing cancer progression and proliferation. Wiest has also developed efficient and effective models to determine mechanistic pathways and to optimize approaches for compound synthesis. His work contributed to the determination of the molecular mechanisms leading to artemisinin resistance in malaria and to better synthesis procedures for a number of pharmaceutical building block compounds.

In addition to his laboratory’s research, Wiest’s role in C-CAS focuses on using machine learning to solve extremely difficult challenges in synthetic chemistry. Researchers utilize AI to determine where best to invest the experimental effort to create new molecules most efficiently. These tools are then shared through open-source clearinghouses with fourteen principal investigators from nine institutions who, along with numerous other collaborators and co-workers, form the core team. Wiest is also a principal investigator of the NSF International Research Experiences for Students program which partners with Heidelberg University to train graduate students in the development of new ligands and reactions for catalytic applications.

Originally published by Rebecca Hicks at chemistry.nd.edu on May 29, 2025.