We are encouraged that these potential issues did not arise in our large-scale ligandbased virtual screen (Tables and) or the largest structure-based virtual screens noted above. Although innovative algorithms will continue to advance virtual screening capa-bilities, probing the practical challenges and potential benefits of computationally-guided screening in synthesize-on-demand chemical libraries necessitates prospective experimental testing. The success of our two prospective screens showcases supervised learning as a powerful approach for navigating large synthesize-on-demand chemical libraries in future drug discovery campaigns.