With the support of The Michael J. Fox Foundation for Parkinson’s Research (MJFF), CD3 and the Lab of Cellular Transport Systems (LCTS), led by Prof. Dr. Peter Vangheluwe at KULeuven teamed up with SandboxAQ, Palo Alto, USA, to leverage Large Quantitative Models (LQMs) and other advanced AI technologies to design and screen new ATP10B activators.
Peter Vangheluwe is a global leader in lysosomal transporters that are implicated in Parkinson’s disease, such as ATP13A2 and ATP10B. As a long-standing MJFF partner, the Vangheluwe lab has helped to better understand the underlying mechanisms of ATP13A2 and ATP10B dysfunction in Parkinson’s disease and pioneered drug discovery efforts on ATP13A2.
ATP10B is a novel candidate risk gene for PD encoding a sphingolipid-transporting ATPase involved in neuronal lipid homeostasis. As a member of the P4-ATPase family, it flips glucosylceramide across the lysosomal membrane, maintaining essential cellular functions. Despite its potential as a therapeutic target, drug discovery efforts face challenges due to ATP10B’s multiunit structural complexity, poor expression, difficult handling and limited understanding of its large-scale reorganization during a complex functional cycle. Targeting ATP10B requires novel approaches to identify small molecule modulators capable of restoring its function.
“Leveraging innovative technology in Parkinson’s research and fostering a collaboration with leading experts is one of the many ways MJFF works to enable a diverse pipeline of treatments for people with Parkinson’s disease,” said Michelle Durborow, head of research operations, MJFF. “We look forward to this collaboration with SandboxAQ and KU Leuven to unlock novel treatments for PD.”
SandboxAQ’s Large Quantitative Models (LQMs) integrate active learning with physics-based scoring functions to create detailed protein profiles and complex interaction matrices. This approach enables rapid in silico high-throughput screening of millions of available compounds to identify potential modulators of ATP10B’s function. Leveraging their expertise in challenging protein targets, SandboxAQ will also support assay development, generate actionable hypotheses for ATP10B activation and advance early-stage drug discovery efforts on a remarkably complex target with major implications in neurodegenerative diseases.
“SandboxAQ’s Large Quantitative Models and AI simulation techniques have proven their ability to rapidly identify ligands and design novel molecules for other challenging neurodegenerative diseases such as Alzheimer’s,” said Nadia Harhen, GM of AI Simulation at SandboxAQ. “KU Leuven hosts one of the world’s foremost research labs for Parkinson’s disease, and we’re eager to apply our Large Quantitative Models to their existing efforts, accelerating new breakthrough treatments for PD.”
KU Leuven researchers, in collaboration with the Centre for Drug Design and Discovery (CD3) of KU Leuven, have taken the first steps to unlock the ATP10B protein for small molecule drug discovery since first describing the gene in 2020. Despite significant advances in understanding the biology of ATP10B, the protein has proven difficult to study. Also, there is little real-world data available related to this specific class of lipid flippases that researchers can use to identify the most effective compounds. SandboxAQ’s Quantitative AI simulations can generate accurate data that enable a more efficient search of the vast chemical space to find and develop compounds with the correct profile.
“The ability to simulate a drug compound’s effects on ATB10B and analyze its mode of action will greatly accelerate our groundbreaking research, helping us achieve with AI technology what lab experimentation alone could not,” said Peter Vangheluwe, professor and head of the Laboratory of Cellular Transport Systems at KU Leuven. “SandboxAQ’s technology has opened the door to a new way of designing novel molecules from the vast chemistry space and testing our hypotheses with unprecedented speed and accuracy, delivering previously unknowable insights that will guide our research.”
We are looking forward to join our forces to bring the field one step closer to a novel treatment!
