Papers › REvoLd: Ultra-Large Library Screening with an Evolutionary Algorithm in Rosetta

REvoLd: Ultra-Large Library Screening with an Evolutionary Algorithm in Rosetta

26 Apr 2024arXiv:2404.17329archive 2025-07-28

Paul Eisenhuth, Fabian Liessmann, Rocco Moretti, Jens Meiler

Ultra-large make-on-demand compound libraries now contain billions of readily available compounds. This represents a golden opportunity for in-silico drug discovery. One challenge, however, is the time and computational cost of an exhaustive screen of such large libraries when receptor flexibility is taken into account. We propose an evolutionary algorithm to search combinatorial make-on-demand chemical space efficiently without enumerating all molecules. We exploit the feature of make-on-demand compound libraries, namely that they are constructed from lists of substrates and chemical reactions. Our novel algorithm RosettaEvolutionaryLigand (REvoLd) explores the vast search space of combinatorial libraries for protein-ligand docking with full ligand and receptor flexibility through RosettaLigand. A benchmark of REvoLd on five drug targets showed improvements in hit rates by factors between 869 and 1,622 compared to random selections. REvoLd is available as an application within the Rosetta software suite.

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