Advancing Alzheimer's Disease Treatment: Synergistic Ligand Combinations Targeting BACE1 via Multi-Ligand Simultaneous Docking

Alzheimer's disease is a progressive neurodegenerative disorder characterized by memory loss, cognitive decline, and behavioral changes, primarily affecting the elderly. Current treatments focus on symptom management as no therapies effectively halt or reverse disease progression. Newer therapies targeting BACE1, a key enzyme in amyloid plaque formation, have shown promise in clinical trials, though they have been limited by side effects and insufficient efficacy in slowing cognitive decline. This is the first study where multi-ligand simultaneous docking (MLSD) was employed to identify potential synergistic inhibitor combinations from among thousands of small molecules that could yield better results than the current phase-III inhibitors of BACE1. The recent phase III drugs such as Atabecestat, Elenbecestat, Lanabecestat, and Verubecestat were considered to be standards for comparison in this study. A library of small molecules with known IC50 values against BACE1 was filtered for flagging Pan-Assay Interference (PAINS) and "Brenk" compounds. Single-ligand docking revealed individual ligand interactions with the protein, forming the basis for creating ligand pairs tested in MLSD. Among these combinations, CHEMBL4078427 and CHEMBL3656158, CHEMBL4078427 and CHEMBL3695732, Verubecestat and CHEMBL3656158, and CHEMBL4078427 and Lanabecestat demonstrated excellent binding affinity of -19.90 kcal/mol, -18.45 kcal/mol, -18.07 kcal/mol, and -17.67 kcal/mol with the protein, which is significantly greater than those of phase-III inhibitors, along with inter-ligand interactions indicative of a synergistic effect. These findings underscore the transformative potential of MLSD in identifying synergistic compound interactions, paving the way for novel combination therapies in the treatment of Alzheimer's disease.

Source: arXiv:2609.04301v1 - http://arxiv.org/abs/2609.04301v1 PDF: https://arxiv.org/pdf/2609.04301v1 Original Link: http://arxiv.org/abs/2609.04301v1