Relaxation of Steric Strains of TTR-Type Amyloid Fibril Inhibitors Radically Changes the Results of Their Virtual Screening

Using the results of virtual ligand screening (VLS) of a representative set of 66834 commercially available drug-like ligands and 8400 di- and tripeptides in the central cavity of Transthyretin (TTR) amyloid fibrils, it has been shown that despite the great chemical diversity, among commercially available drug-like organic compounds and ultrashort peptides (USPs), only 7 USPs are able to bind in the central cavity of TTR amyloid fibrils, thus preventing the growth of amyloid fibrils. The results of VLS also show that the relaxation of ligand steric strains in the obtained complexes not only significantly improves docking scores but also radically (>50%) changes the main result of VLS, the molecular composition of 1% of the best ligands. Thus, the relaxation of steric strains after VLS can more than double the effectiveness of VLS in the development of new drugs.