Molecular dynamics (MD) simulations were used to characterize the binding of drug molecules to the V122I mutant of the protein transthyretin. This protein is associated with the disease Familial Amyloid Cardiomyopathy in which amyloid plaques form in the heart. Recently the drug candidate AG10 was synthesized. This compound was subsequently found to bind to the V122I transthyretin mutant, stabilize the protein tetramer, and prevent transthyretin amyloidosis. This study used MD simulations to study how the AG10 molecule and its decarboxy and N-methyl derivatives bound to V122I transthyretin. The MD simulations showed that AG10 interacted favorably with the protein receptor by forming a stable, two-point hydrogen bonding interaction within the protein’s binding pocket. A two-point interaction also formed with N-methyl-AG10, although its free energy of receptor binding was lower than AG10. In decarboxy-AG10, the two-point interaction was disrupted and the ligand changed both its position and conformation within the binding pocket. This poster will present these results and discuss their relevance to the discovery of other drug therapies for transthyretin-related diseases.

Molecular dynamics simulation study of AG10 binding to the Val122Ile transthyretin variant

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.