Exploring the orphan immune receptor TREM2 and its non-protein ligands: In silico characterization

• Published in: Chemistry and physics of lipids 2025-01, Vol.266, p.105449, Article 105449
• Main Authors: Dantas, Pedro Henrique dos Santos, Costa, Vinícius Alexandre Fiaia, Felice, Andrei Giacchetto, Sousa, Eduarda Guimarães, de Oliveira Matos, Amanda, de Castro Soares, Siomar, Silva-Sales, Marcelle, Junior-Neves, Bruno, Sales-Campos, Helioswilton
• Format: Article
• Language: English
• Subjects: CDR; Drug discovery; Ligand; MMGBSA; Molecular docking; TREM-2
• ISSN: 0009-3084; 1873-2941; 1873-2941
• DOI: 10.1016/j.chemphyslip.2024.105449

The triggering receptor expressed on myeloid cells 2 (TREM2) is an immunoreceptor that interacts with a wide range of non-protein ligands, and it has been implicated in infectious and non-infectious diseases. However, there is a limited understanding on how this receptor interacts with non-protein ligands and the potential of such information to develop new therapeutic drugs. Therefore, our study aimed to elucidate the interactions between TREM2 and its non-protein ligands. First, we searched PubChem and Protein Data Bank (PDB) for TREM2 structures and their corresponding non-protein ligands. Subsequently, these structures were employed in molecular docking and MM/GBSA simulations with the Maestro software and molecular dynamics in GROMACS software. TREM2 was subsequently subjected to druggable site prediction using CavityPlus and receptor-based drug repositioning via the DrugRep server. TREM2 interacts with high affinity with its 12 non-protein ligands, with affinity values ranging from −33.01 kcal/mol for phosphatidylserine to −80.87 kcal/mol for cardiolipin (CLP). In molecular dynamics simulations, homodimeric TREM2 bound more stably to its lipid ligands, such as CLP and PSF, whereas it was unstable when unbound. The interactions between the receptor and its non-protein ligands were driven by the complementarity determining regions (CDR) 1 and 2, that are present in the hydrophobic and positively charged regions, highlighting that the Y38–R98 region is fundamental for drugs targeting TREM2. Our data underscore the significance of TREM2's CDRs in recognizing its ligands, suggesting they as promising targets for prospective drug design studies. [Display omitted] •Cardiolipin was the compound that interacted with the greatest affinity and stability to TREM2.•TREM2 antigen recognition is mediated by CDR1 and CDR2 regions.•The region between the residues Y38 and R98 is highly druggable and suitable for drug repositioning.