Design of transthyretin amyloidosis inhibitors: A docking and virtual screening approach

Amyloidosis consists in the extracellular deposition of protein in a typical fibrillar form. Hereditary amyloidosis is a rare, often fatal, form of systemic amyloidosis, producing neurol. and/or cardiac disorders and is due to a mutation in the gene encoding the plasma transthyretin (TTR) protein. Because more than 95% of TTR is produced by the liver, the liver transplantation is the only established treatment to halt amyloid formation. TTR is a homo tetrameric protein, made up of four subunits rich in beta-sheets, which is present both in human plasma and in the cerebrospinal fluid as thyroxine (T4) carrier and is involved in the transport of retinol with the retinol-binding protein. Recently several small nonsteroidal anti-inflammatory drugs (NSAIDs) have been reported to bind to TTR in vitro, in the T4 binding channel that runs through the TTR tetramer and, consequently, are considered to stabilize TTR and to prevent amyloid fibril formation. However, the binding with the other plasma proteins compromises their use as therapeutic agents for TTR amyloidosis. In the present work, we report a computational study performed to design new inhibitors, in which the anti-inflammatory activity is lowered or absent. We analyzed the best docking protocol through a cross-docking performed into 23 crystal structures of TTR-inhibitor complexes and developed a pharmacophoric model using the crystallog. poses of these ligands. Finally, we tested the reliability of our pharmacophoric model through a screening of about 380 known ligands and applied this procedure as a pre-filter step for a virtual screening