Identification of Transthyretin Fibril Formation Inhibitors Using Structure‐Based Virtual Screening

• Published in: ChemMedChem 2017-08, Vol.12 (16), p.1327-1334
• Main Authors: Ortore, Gabriella, Martinelli, Adriano
• Format: Article
• Language: English
• Subjects: Amyloid; Amyloid - metabolism; amyloidosis; Binding Sites; Cerebrospinal fluid; Computation; Computer applications; Crystal structure; Crystallography, X-Ray; Databases, Chemical; Docking; Environmental degradation; fibril formation; Fibrils; Humans; Ligands; Molecular Docking Simulation; Prealbumin - antagonists & inhibitors; Prealbumin - metabolism; Protein Binding; Protein Structure, Tertiary; Thyroxine; Transthyretin; virtual screening
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201700051

Transthyretin (TTR) is the primary carrier for thyroxine (T4) in cerebrospinal fluid and a secondary carrier in blood. TTR is a stable homotetramer, but certain factors, genetic or environmental, could promote its degradation to form amyloid fibrils. A docking study using crystal structures of wild‐type TTR was planned; our aim was to design new ligands that are able to inhibit TTR fibril formation. The computational protocol was thought to overcome the multiple binding modes of the ligands induced by the peculiarity of the TTR binding site and by the pseudosymmetry of the site pockets, which generally weaken such structure‐based studies. Two docking steps, one that is very fast and a subsequent step that is more accurate, were used to screen the Aldrich Market Select database. Five compounds were selected, and their activity toward inhibiting TTR fibril formation was assessed. Three compounds were observed to be actives, two of which have the same potency as the positive control, and the other was found to be a promising lead compound. These results validate a computational protocol that is able to archive information on the key interactions between database compounds and TTR, which is valuable for supporting further studies. Rapid and accurate! Inhibitors of transthyretin (TTR) fibril deposition were identified thanks to a structure‐based virtual screening of the entire Aldrich Market Select database. The first results of this protocol, despite the unique peculiarity of the TTR site with its symmetry and multi‐binding mode, allowed the detection of two very active inhibitors and one scaffold for optimization. Much information, however, is still stored in the outputs.