Development of MEIS-HD inhibitors. (A) Alignment of TALE type HDs. The amino acid sequences of each TALE family proteins collected from NCBI. Multiple alignments were done using the “constraint based multiple alignment tool” (COBALT). Highly conserved residues are marked with *. Note that there are several 100% conserved residues across TALE family of proteins. (B) Molecular docking of MEIS homeodomain. MEIS homeodomain was docked with small molecules in two grid boxes, whole surface included grid box and DNA binding residues grid box. Whole surface search box is performed to determine and eliminate small molecules non-specifically binds to homeodomain versus DNA binding residues. Dimensions in the grid box are provided in angstroms. (C) Enrichment analysis. Percent enrichment and enrichment factor ratio analysis of hits in homeobox library of small molecules docked into MEIS HD compared to random (ZINC drugs-now set) or unrelated (Lopac1280 set, or PubChem training set) libraries. (D) Analysis of MEISi hit small molecules. MEIS hit molecules analyzed for structural similarity based on substructure key-based 2D Tanimoto similarity. (E) Two clusters of MEISi hit molecules were identified. Structures and CID numbers are provided.