Ultra-Large-Scale Virtual Screening

Recently, make-on-demand chemical libraries and spaces began to grow into the billion scale, resulting in a surge of ultra-large ligand- and receptor-based virtual screening (VS) approaches. This chapter introduces state-of-the-art screening compound resources with up to 290 trillion compounds and provides examples of ultra-large VS campaigns performed between 2019 and 2024. We emphasize key considerations for the planning stage of your own ultra-large VS and the choice of the computing environment. Some of the covered highlights include 2D similarity searches in nonenumerated spaces, 3D shape screening, giga-scale brute-force docking, and screening acceleration strategies either leveraging machine learning and deep learning or relying on the reagent-space of recent make-on-demand combinatorial libraries. To scrutinize whether and when “bigger is better,” we discuss the critical challenge of hit triage on the ultra-large scale and conclude with future perspectives for VS in the face of continuing library growth.