3D-QSAR Modeling and Molecular Docking Study on Small Molecule Stat3 Inhibitors, Src Homology 2 Domain Binders

The Src Homology 2 (SH2) domain of Stat3, which acts as therapeutic target, are used to treat multiple myeloma (MM). The activities of Tolyl-N-alkyl derivatives as Stat3 inhibitors were analyzed, using the three-dimensional quantitative structure-activity relationship (3D-QSAR) and molecular docking method. The final CoMFA and CoMSIA models yielded statistically significant results with the cross-validated correlation coefficients q2 of 0.566 and 0.644, the correlation coefficients r2 of 0.945 and 0.967, respectively. In addition, we used the CoMFA and CoMSIA models to design a series of new inhibitors. Molecular docking explored the binding mode between the receptor protein and the ligand. The docking results demonstrated that the key amino acid residues (Lys626, Gln635, Ser636, Glu625, Trp623, Glu638 and Tyr657) were found in binding site. The ligand was located in the hydrophobic binding region formed by the amino acid residues: Val637, Phe716, Pro715, Ile659, Tyr640 and Pro639. The obtained information from computational studies can offer a good guideline for designing novel Stat3 inhibitors.