Transthyretin Induced Amyloidosis Interactions, Mechanisms and Potent Drugs Design

Abstract

Aging society faces the problem of deterioration of lifes' quality. Thus the research targeted on improvement of humans health is important and challenging task. The senile systematic amyloidosis, disease that is caused by unnaturally forming fibrils, affects about 25% of population over 80th year of life and may be lethal.One of proteins involved in forming amyloidoic fibrils is transthyretin (TTR). TTR molecules occur in plasma and cerebral fluid [1] as a homotetramer, in healthy persons are responsible for thyroxine and retinol transport. TTRs' stability is essential to avoid TTR-based amyloidosis (a-TTR). A-TTR cascade is well known: the initial step of the whole process is dissociation of a tetramer into two dimers, then into monomers and - at the end - the monomer has to misfold. Such monomers are prone to fibril formation. A-TTR cascade may be accelerated by numerous point mutations [2].Here we present results of our wide range MD investigations of various TTR variants - WT and medically relevant variants. We use protocol similar to these published in [3]. We try to determine the stabilizing influence of some new potent drugs - members of flavonoids family located within TTR channels., using our newly developed CHARMM [4] force field compatible ligand parameters set. We describe details of interactions between TTR molecules, ligands' stabilisation properties and early-stage amyloidosis mechanisms at an atomic level.This work was supported by NCN grant no. N202 262083 (WN) and Faculty of Physics, Astronomy and Informatics, NCU grant no. 1623-F (RJ).[1] G.A. Hagen,et al. Endocrinol Metab, 1973, 37, 415-22.[2] C.E. Bulawa, et al., Proc Natl Acad Sci USA, 2012, 109(24), 9629-34.[3] K. Mikulska et al, Chem. Phys. Letters, 2011 521, 134-137.[4] A.D. MacKerrel Jr., et al. J Phys Chem B, 1998, 102, 3586-3616.