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

Sungwoo Cho1, Baljit Kaur1, Kevin Lam2

  • 1Department of Radiology, Molecular Imaging Innovations Institute (MI3), Weill Cornell Medicine, New York, New York, USA.

Chemmedchem
|January 28, 2026
PubMed

Insights

Researchers identified EN020, a novel small-molecule modulator of Triggering Receptor expressed on myeloid cells 2 (TREM2). This compound enhances microglial phagocytosis, offering a new therapeutic avenue for Alzheimer's disease (AD).

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 (KD 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.
Keywords:
Alzheimer's diseaseTREM2biophysical validationdrug discoveryvirtual screening

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