A Combination of Pharmacophore and In silico Approaches for Identification of Potential Transthyretin Amyloidosis Inhibitors

Transthyretin (TTR) is a homotetrameric plasma protein that has been associated with numerous human amyloid diseases. Although Tafamidis has recently been approved for the treatment of TTR familial amyloid polyneuropathy (FAP), there is still a need persists for drugs that are more effective in the treatment of TTR amyloidosis diseases. Therefore, we propose ligand-based and structure-based pharmacophore models were generated in this study based on the chemical features present in active TTR amyloidosis inhibitors and the binding information of TTR-DZ2 complex, respectively, to screen chemical databases to identify potential drug candidates. Subsequently, the hits with good fit values were filtered based on absorption-distribution-metabolism-excretion-toxicity (ADMET), as well as molecular docking and receptor- specific scores. Furthermore, their binding stabilities were validated using 10-ns molecular dynamics (MD) simulations. Finally, only 2 compounds (NSC 246123 and Compound 52292) that exhibited higher binding affinities than that of Tafamidis were identified as potential leads. To our knowledge, this report is the first pharmacophorebased virtual screening study presenting the discovery of novel TTR amyloidosis inhibitors. The findings should be a useful guide for the rapid identification of novel therapeutic agents from chemical databases.