Laufer Center Seminar - Dr. Celia Schiffer
Celia A. Schiffer, PhD
Arthur F. and Helen P. Koskinas Professorship in Biochemistry & Molecular Biotechnology; Professor & Chair of Biochemistry & Molecular Biotechnology; Director Institute for Drug Resistance (IDR)
UMass Chan Medical School, Department of Biochemistry and Molecular Biotechnology
November 21, 2025 at 12:30 PM
Laufer Center Lecture Hall 101
Tittle: Pre-emptively Avoiding Drug Resistance: Lessons from viral proteases
Abstract:
Drug resistance threatens many critical therapeutics through mutations in the enzyme drug target. Mutations can occur both within the active site of an enzyme and at sites distal from the active site. Enzymes are dynamic, recognizing substrates and turning over products. This functional constraint determines what mutations can be tolerated. The substrate envelope can define a probability map that can pre-emptively predict where active site mutations are likely to occur. However, the molecular mechanisms by which combinations of mutations, especially those distal from the active site, alter drug binding to confer resistance are poorly understood and thus difficult to counteract. Through experimental and computational studies on viral proteases, we are combining the substrate envelope with machine learning strategies that incorporate parallel molecular dynamics to uncover the molecular mechanisms of drug resistance. This physics-based strategy of identifies critical features that serve as bellwethers of affinity and can be combined with the substrate envelope to guide inhibitor design that decreased the probability of resistance.
