Abstract

Transthyretin (TTR) is protein produced in liver that carries the hormone thyroxine and retinol through the blood and spinal fluid. Familial Amyloidal Cardiomyopathy is a genetic disorder causing TTR to misfold and form into amyloid plaques on the muscle walls of the heart. One instance of misfolding involves a point mutation involving Valine-122 to Isoleucine, which is present in 3 % of African Americans. There are few FDA-approved drugs to treat FAC; however, recent studies of drug interactions with TTR utilizing molecular dynamics simulations have been done. Some of these studies investigate the interactions between the drug molecule TKS-14 and TTR. In those simulations, TTR residue Lys-15 was determined to be and important residue for hydrogen bonding between TTR and TKS-14. This project investigated further the importance of this interaction and any hydrophobic interactions that occur between TKS-14 and TTR. The latter studies were done by modifying the center pyrazole ring in TKS-14. When Lys-15 was mutated to leucine, the TKS-14 molecule remained in the TTR binding pocket. However, the ligand-TTR binding energy was reduced. These results will be presented along with studies mapping the TKS_14-TTR intermolecular interactions.