Abstract: Disclosed is a computer-implemented method for identifying small molecule binders within a DNA-encoded library (DEL) dataset. Said method comprises: obtaining a DEL dataset comprising enriched compounds; grouping enriched compounds into one or more compound groups based on a grouping criterion selected from at least one of: chemotype, library, enrichment level, or linear feature; generating a plurality of three-dimensional (3D) conformers, for each enriched compound in each compound group; comparing generated 3D conformers within one or across two or more compound groups to identify consensus overlays based on similarity metrics exceeding a predefined threshold; and selecting small molecule compounds forming said cross-group consensus overlays as small molecule binders having affinity for a target of interest. Disclosed also is a system for identifying small molecule binders within a DEL dataset.