Topic Overview:
Medicinal chemists are the architects of modern drug design and discovery. Using atoms as their basic construction materials and hydrogen bonds, covalent bonds, charge-charge interactions, and hydrophobic interactions as their cement, chemists envision, design, and build biologically relevant molecules that could potentially improve the human condition. Keeping with the traditional Bauhaus design principle, “form follows function,” drug-like compounds must not only reach their specific targets but must also be potent, water soluble, stable, lipophilic, and cause few side effects. In this lecture, Dömling will present some of the modern tools chemists use to design and build effective compounds and will demonstrate their applications with his particular target of interest―p53 and its interaction with negative regulators mdm2 and mdm4.

p53 is a powerful growth suppressive and pro-apoptotic molecule that is frequently inactivated in cancer due to mutations or defective cell signaling. Restoring its tumor suppressive function is a major goal of modern oncology. Toward this goal, Dömling’s laboratory designs and synthesizes small molecules that disrupt the interactions of p53/mdm2 and p53/mdm4. Together with collaborators, they recently solved six co-crystal structures of their small molecule inhibitors bound to mdm2 and the first ever co-crystal structure of an mdm4-antagonist complex. Dömling will present cell-based activity and initial stability data of these compounds (prerequisites to animal pharmacokinetics and efficacy studies).