Deep Origin’s docking and molecular dynamics (MD) simulations have successfully rationalised researchers’ work identifying a potent compound to switch on cell-death programmes in diffuse large B cell lymphoma (DLBCL). 

The study was led by researchers at Stanford University and the University of Texas MD Anderson Cancer Center.  

It describes the development of KAT-TCIPs (lysine acetyltransferase transcriptional/epigenetic chemical inducers of proximity), which act as molecular glues that induce a ternary complex between the gene-activating enzymes p300/CBP and the cancer driver B cell lymphoma 6 (BCL6).  

The interaction is of interest to cancer researchers because it supports potent cell killing. Molecular glues, a type of CIP facilitating the assembly of unrelated proteins, is a fast-emerging drug class. 

The researchers at Deep Origin used docking software, MD simulations, and quantum mechanical calculations to assess a library of 17 compounds. First, the ternary complexes were generated by docking each compound at the protein-protein interface and selecting poses with the best docking scores. Then, Deep Origin’s molecular dynamics engine was used to run 300-nanosecond simulations for each ternary complex to refine the initial pose and generate an ensemble of structures.  

Finally, the quantum mechanical calculations were utilised to calculate linker strain energy for each compound based on the obtained structural ensembles. The team ranked the compounds by the energetic cost that they incur when forming the ternary complex. 

Great strides in computational prediction 

The compound that incurred the least energetic cost killed lymphoma cells at sub-nanomolar concentrations (IC50 0.80 nM). 

The computational results aligned with laboratory tests. In a mouse xenograft model of the disease, the selected compound led to complete or near-complete tumour clearance, and in immunised mice it depleted germinal centre B cells, which express high levels of BCL6 and serve as a model for certain lymphomas, with no overt organ toxicity. 

“Deep Origin’s computational simulations flagged the compound that would kill cancer cells most effectively – matching results achieved at the bench,” said Dr Garegin Papoian, Co-Founder and Chief Scientific Officer of Deep Origin. “This is a predictivity goal of in silico drug discovery – to determine the candidates most likely to achieve desired results prior to wet lab experimentation. At Deep Origin, we’ve made great strides in computational prediction by combining the rigor of physics-based simulation with the speed and scale of AI, outperforming industry benchmarks. This was a meaningful real-world test of our systems.”