TRPM8 ligand modification

Abstract

Introduction. In silico methods make it possible to detect low molecular weight ligands with a high affinity for a protein, but cannot answer the question of whether the ligand is its agonist or antagonist.Aim. Use of a virtual modification of the TRPM8 agonist menthol to solve this problem.Materials and methods. The structure of menthol was modified using the PyMol computer simulation program, removing the hydroxy group in the meta position and adding two new hydroxy groups in the ortho positions. To identify the features of the docking of menthol and its modified derivative in the TRPM8 molecular pocket, the Galaxy7TM virtual molecular laboratory service was used, which allows to determine which amino acid residues the ligand interacts with by using flexible intermolecular docking methods.Results. Menthol and its modified derivative form stable complexes with TRPM8, but the hydrogen bonds of the hydroxyl groups of the ligands occur with different amino acid residues.Conclusion. Using in silico methods, it was possible to modify the structure of menthol and obtain a ligand that binds to TRPM8 differently than natural. The modified ligand does not bind to the key amino acid of the TRPM8 active site, tyrosine 745, and therefore should exhibit antagonist properties. The proposed strategy is universal, will accelerate the search for ligands to various proteins and will facilitate the accelerated search for potential drugs by in silico methods.