CBE 298 Seminar: Enabling Inverse Design of Molecules to Drive Defined Physiological Outcomes - A Critical Role for Systems Modeling in a Data-Driven World

Abstract: Drug discovery is a molecular search task with a challenging objective: modify the function of a complex biological system to interrupt disease processes. Conventionally, it is a costly, high failure-rate process – with molecular candidates clearing preclinical safety and efficacy hurdles only to fail upon delivery to humans. This happens partly because early screens in the discovery pipeline fall short of capturing the ultimate therapeutic value of new molecular candidates. For a molecule to become a successful drug, it should: (1) bind to a desired target protein; (2) be deliverable from a desired site of administration (oral, intravenous, etc.) to the physiological site of activity, with sufficient concentration for a sufficient duration of time; and (3) promote the desired pharmacological effect without causing unwanted toxicity. The chemical space that meets one of these objectives likely requires compromises in another, as binding, delivery and activity depend on coupled and dynamic biophysical and biochemical interactions. In this presentation, I will discuss our work on integrating mechanistic systems models with data-driven machine learning and generative AI models to empower physiology-informed design of potential therapeutics.

Bio: Belinda Akpa is a senior staff scientist in Quantitative Systems Biology at ORNL and joint associate professor in chemical and biomolecular engineering at the University of Tennessee. She holds a B.A., M.Eng, and doctorate in chemical engineering from the University of Cambridge (UK). A highly interdisciplinary researcher, her current interest is in developing mathematical frameworks that integrate scarce and heterogeneous data to connect molecular phenomena to dynamic physiological outcomes. Akpa is broadly interested in computational biology, but more specifically in how mechanistic mathematical models can be used to inform targeted experimental strategies. To date, her work has touched the fields of pharmacology/toxicology, membrane biophysics, plant physiology and forensic anthropology.