Discovery of High-Affinity Amyloid Ligands Using a Ligand-Based Virtual Screening Pipeline

Fibrillar protein aggregates are characteristic of neurodegenerative diseases but represent difficult targets for ligand design, because limited structural information about the binding sites is available. Ligand-based virtual screening has been used to develop a computational method for the selection of new ligands for Aβ(1-42) fibrils, and five new ligands have been experimentally confirmed as nanomolar affinity binders. A database of ligands for Aβ(1-42) fibrils was assembled from the literature and used to train models for the prediction of dissociation constants based on chemical structure. The virtual screening pipeline consists of three steps: a molecular property filter based on charge, molecular weight, and log<i>P</i>; a machine learning model based on simple chemical descriptors; and machine learning models that use field points as a 3D description of shape and surface properties in the Forge software. The three-step pipeline was used to virtually screen 698 million compounds from the ZINC15 database. From the top 100 compounds with the highest predicted affinities, 46 compounds were experimentally investigated by using a thioflavin T fluorescence displacement assay. Five new Aβ(1-42) ligands with dissociation constants in the range 20-600 nM and novel structures were identified, demonstrating the power of this ligand-based approach for discovering new structurally unique, high-affinity amyloid ligands. The experimental hit rate using this virtual screening approach was 10.9%.