Active learning driven prioritisation of compounds from on-demand libraries targeting the SARS-CoV-2 main protease

FEgrow is an open-source software package for building congeneric series of compounds in protein binding pockets. For a given ligand core and receptor structure, it employs hybrid machine learning/molecular mechanics potential energy functions to optimise the bioactive conformers of supplied linkers and functional groups. Here, we introduce significant new functionality to automate, parallelise and accelerate the building and scoring of compound suggestions, such that it can be used for automated <i>de novo</i> design. We interface the workflow with active learning to improve the efficiency of searching the combinatorial space of possible linkers and functional groups, make use of interactions formed by crystallographic fragments in scoring compound designs, and introduce the option to seed the chemical space with molecules available from on-demand chemical libraries. As a test case, we target the main protease (Mpro) of SARS-CoV-2, identifying several small molecules with high similarity to molecules discovered by the COVID moonshot effort, using only structural information from a fragment screen in a fully automated fashion. Finally, we order and test 19 compound designs, of which three show weak activity in a fluorescence-based Mpro assay, but work is needed to further optimise the prioritisation of compounds for purchase. The FEgrow package and full tutorials demonstrating the active learning workflow are available at https://github.com/cole-group/FEgrow.