A Novel Multi-Tiered Hybrid Virtual Screening Pipeline for the Discovery of WDR5-MLL1 Interaction Disruptors in Precision Cancer Therapy

WD Repeat-containing protein 5 (WDR5) is a critical companion for the mixed lineage leukemia (MLL) complex, essential for epigenetic regulation and implicated in various cancers, particularly leukemia. Overexpression of WDR5 in malignant tissues is linked to poor clinical outcomes and enhanced cancer cell proliferation. Its interaction with the MLL1 protein occurs via the WDR5 protein, which is vital for the MLL complex’s methyltransferase activity. Recent studies highlight the WIN site as a promising therapeutic target, especially for MLL-rearranged leukemia. In this study, we investigated the structural dynamics of the WDR5-MLL1 complex and aimed to identify potential small-molecule inhibitors targeting the WIN site, to develop novel therapeutic strategies for leukemia and other WDR5 protein-dysregulated cancers. Utilizing the crystal structures of the WDR5 and MLL1, we screened around one million synthetically available compounds from ChemDiv, Enamine, and Specs small molecule libraries. The computational analysis was conducted through comprehensive all-atom molecular dynamics (MD) simulations to evaluate ligand–receptor interaction affinities and involved binding residues. The simulations revealed key participating amino acid residues while quantifying binding affinities using the Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) approach. Steered molecular dynamics (sMD) simulations were further conducted to assess the stability of ligand–receptor interactions of the selected top-compounds. Additionally, novel potential compounds were generated using BRICS fragmentation and Monte Carlo tree search algorithms. Our analysis revealed diverse interaction patterns and potential inhibitory mechanism among the screened compounds. Several compounds, such as Z88418521 and Z116334910, displayed stronger predicted binding affinities than the reference molecule IA9, exhibiting competitive and allosteric modulation of the WDR5-MLL1 complex interaction. A thorough analysis of WDR5 protein and WDR5-MLL1 interactions and their conformational changes offered valuable perspectives on targeting the WDR5-MLL1 complex interaction. Thus, this study profiles the molecular alterations that occur during WDR5-MLL1 complex inhibition, offering crucial mechanistic insights that establish a solid framework for developing targeted treatments for MLL-rearranged leukemia. The distinctive binding characteristics and conformational dynamics exhibited by the identified compounds provide a compelling foundation for future experimental approaches to leukemia intervention.