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

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• Triggering receptor expressed on myeloid cells 2 (TREM2) is crucial for microglial function and neuroprotection in 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 a structure-based virtual screening approach.
• To evaluate the functional activity of identified compounds in enhancing microglial phagocytosis.

Main Methods:

• Employed a structure-based virtual screening workflow targeting a putative allosteric site on TREM2.
• Utilized PyRod-derived pharmacophores from molecular dynamics simulations for virtual screening.
• Screened the Enamine Collection (ESC) and validated hits using TRIC assays, MST, and SPR.

Main Results:

• Identified EN020 as a top-hit small-molecule TREM2 modulator with demonstrated binding affinity (K_D of 14.2 µM via MST).
• EN020 significantly enhanced microglial phagocytosis in BV2 cells, surpassing the efficacy of the known agonist VG-3927.
• Preliminary structure-activity relationship (SAR) studies indicated limited tolerance for scaffold modifications, with T2V002 retaining partial binding.

Conclusions:

• EN020 represents a novel, functionally active small-molecule TREM2 modulator.
• This discovery provides a promising lead compound and a framework for developing new therapeutics for AD and related neurodegenerative disorders.