Potential GSK-3 binding of two novel pyrazolo[3,4-g]isoquinoline derivatives: Synthesis, structural characterization, and computational studies

Two novel pyrazolo[3,4-g]isoquinolines (III and VI) have been synthesized, and their corresponding structures were confirmed using X-ray crystallography. The short intermolecular contacts in the crystals of III and VI were identified through the analysis of the Hirshfeld surface and fingerprint plots. These analyses reveal the involvement of CS, CO, and the amine functional groups in the intermolecular hydrogen bonds and that the major contact is H···H with an overall contribution of 53-57 %. The optimized geometries and the global reactivity properties of both molecules were generated using DFT methods at the PCM-B3LYP/6-31+G(d,p) level of theory. The geometrical parameters of both molecules are relatively well reproduced with correlation coefficients between the experimental and calculated bond lengths, bond angles, and torsion angles in the ranges 90-99 %. Both compounds show similar electronic and molecular properties. Treatment for neurodegenerative and psychiatric illnesses increasingly involves pharmacologically the inhibition of glycogen synthase kinase-3 (GSK-3). Here we have focused on understanding the binding ability of our molecules with GSK-3 using molecular docking. III and VI exhibit strong binding affinity toward the GSK-3 binding site, and they formed stable complexes with their amino acids of free binding energies of 7.8 and -7.1 kcal/mol, respectively. Molecular dynamics studies were performed to investigate the stability of III-GSK-3 and VI-GSK-3 complexes. MD analysis of the RMSD, RMSF, and rGyr plots demonstrate the stability of III and VI within the binding site of GSK-3. ADMET analyses reveal that both compounds may exhibit drug-like properties such as high absorption, polarity, lipophilicity, and oral bioavailability.