"Optimizing Drug-Target Interactions: Challenges and Opportunities”, Prof. Joseph Loscalzo, Brigham and Women’s Hospital Harvard Medical School, Boston, Massachusetts

The development of drug therapies holds many challenges beyond the synthesis of the drug. For example, diffusion of drug compounds through the macromolecule-rich cytoplasm to their specific targets is a complicated process that does not follow conventional laws of diffusion. Drug diffusion in the cytosol is anomalous, owing to low(er) affinity, high capacity interactions with other (macro)molecular species in the cell, resulting in quite different binding interactions and kinetic constants than predicted from isolated studies of the drug and its purified target in dilute solution. Here, we present data supporting these anomalous behaviors, and illustrate their consequences for expected drug effects in vivo. Yet another challenge to optimizing effective drug-target interactions arises in studies of combination drug therapies, where screening becomes exponentially more complicated as the number of drugs in the combination increases. With personalized medicine requiring tailored combination therapies in many diseases for optimal efficacy, this important problem warrants novel solutions. Here, we demonstrate a novel convection gradient approach to analyzing combination drug therapies in a system in which the uptake and effect of bar-coded drugs over a range of concentrations are monitored in single cells, dramatically reducing the screening time and experimental resources required for studying a wide range of concentrations and combinations. Lastly, the power of the placebo effect in mitigating the measured efficacy of a drug in vivo presents another major challenge to optimizing drug development. Our work involving molecular (protein-protein) interaction networks has given us new insight into the placebo effect and shown that it has a molecular basis that can be understood and therapeutically exploited in many diseases.


October 20th 2022, at 10,00 a.m., Room A department of chemistry and drug technologies (CU019)

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