We followed a comprehensive computational strategy to understand and eventually predict the structure-activity relationship of thirty-three 1,3-disubstituted imidazole [1,5-α] pyrazine derivatives described as ATP competitive inhibitors of the IGF-1 receptor related to Ewing sarcoma. The quantitative structure-activity relationship model showed that the inhibitory potency is correlated with the molar volume, a steric descriptor and the net charge calculated value on atom C1 (q1) and N4 (q4) of the pharmacophore, all of them appearing to give a positive contribution to the inhibitory activity. According to experimental and calculated values, the most potent compound would be 3-[4-(azetidin-2-ylmethyl) cyclohexyl]-1-[3-(benzyloxy) phenyl] imidazo [1,5-α]pyrazin-8-amine (compound 23). Docking was used to guess important residues involved in the ATP-competitive inhibitory activity. It was validated by 200 ns of molecular dynamics (MD) simulation using improved linear interaction energy (LIE) method. MD of previously preferred structures by docking shows that the most potent ligand could establish hydrogen bonds with the ATP-binding site of the receptor, and the Ser979 and Ser1059 residues contribute favourably to the binding stability of compound 23. MD simulation also gave arguments about the chemical structure of the compound 23 being able to fit in the ATP-binding pocket, expecting to remain stable into it during the entire simulation and allowing us to hint the significant contribution expected to be given by electrostatic and hydrophobic interactions to the ligand-receptor complex stability. This computational combined strategy here described could represent a useful and effective prime approach to guide the identification of tyrosine kinase inhibitors as new lead compounds.
Keywords: Cluster analysis; Docking; Ewing sarcoma; Molecular dynamics simulations; QSAR; Virtual screening.