In silico design of novel potential isonicotinamide-based glycogen synthase kinase-3β (GSK-3β) inhibitors: 3D-QSAR, molecular docking, molecular dynamics simulation and ADMET studies

Abstract

GSK-3β is a highly sought-after target in drug development and its inhibitors are potential candidates for treatment of various diseases. Isonicotinamide derivatives have been proven to be promising leads for GSK-3β inhibitor discovery. To explore the structure–activity relationship and further design inhibitors with higher activity, a series of recently reported isonicotinamide-based GSK-3β inhibitors were chosen to perform 3D-QSAR analyses. The 3D-QSAR models were constructed using comparative molecular field analysis (CoMFA: q² = 0.505, ONC = 5, r² = 0.935, F = 138.934, SEE = 0.195, and r_pred² = 0.914) and comparative molecular similarity index analysis (CoMSIA: q² = 0.544, ONC = 6, r² = 0.970, F = 212.137, SEE = 0.136, and r_pred² = 0.850) methods. Based on the analysis of 3D-QSAR models, more than 50 new compounds were designed, among which 8 compounds exhibited higher predicted activity than compound 20 (the most active compound in the dataset). Notably, compounds 3X and 9X were found to be potential inhibitors through molecular docking and MD simulation studies. Additionally, both compounds were predicted to have favorable pharmacokinetic properties and high synthetic feasibility. The main contribution of our work was the generation of 3D-QSAR models with good predictivity and the establishment of structure–activity relationships for isonicotinamide-based GSK-3β inhibitors. Besides, the newly designed compounds hold potential as GSK-3β inhibitors and merit further exploration.