Structure-Based Virtual Screening Identifies TREM2-Targeted Small Molecules that Enhance Microglial Phagocytosis

Area of Science:

• Neuroscience
• Pharmacology
• Drug Discovery

Background:

• Triggering receptor expressed on myeloid cells 2 (TREM2) is crucial for microglial function and neuroprotection in neurodegenerative diseases like Alzheimer's disease (AD).
• Existing therapeutic strategies for TREM2 primarily involve antibodies, with limited development of small molecule modulators.

Purpose of the Study:

• To identify novel small molecule modulators of TREM2 using structure-based virtual screening.
• To characterize the functional activity of identified compounds, particularly their effect on microglial phagocytosis.

Main Methods:

• Structure-based virtual screening of the Enamine Collection targeting a putative allosteric site on TREM2.
• Molecular dynamics simulations and PyRod-derived pharmacophores guided the screening workflow.
• Binding affinity assays (MST, SPR) and cellular assays (microglial phagocytosis in BV2 cells) were employed for characterization.

Main Results:

• Virtual screening identified 20 candidate compounds, with three showing TREM2 binding.
• The top hit, EN020, demonstrated significant enhancement of microglial phagocytosis, outperforming the known agonist VG-3927.
• Preliminary structure-activity relationship studies indicated limited tolerance for scaffold modifications, with T2V002 retaining partial binding.

Conclusions:

• EN020 is a novel, functionally active small molecule TREM2 modulator.
• This discovery provides a promising lead compound for developing new therapeutics for Alzheimer's disease and related disorders.
• The study establishes a framework for rational optimization of small molecule TREM2 modulators.