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

## TL;DR

This study develops a new computational pipeline to find drugs that disrupt the WDR5-MLL1 protein interaction, a key target in leukemia treatment.

## Contribution

A novel multi-tiered hybrid virtual screening pipeline was developed to discover WDR5-MLL1 interaction disruptors for precision cancer therapy.

## Key findings

- Compounds like Z88418521 and Z116334910 showed stronger predicted binding affinities than the reference molecule IA9.
- Molecular dynamics simulations revealed key amino acid residues and binding affinities in the WDR5-MLL1 complex.
- The study identified potential allosteric and competitive modulators of the WDR5-MLL1 interaction.

## Abstract

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.