Discovery of Small‐Molecules as Potential GSK‐3β Inhibitors for the Treatment of Alzheimer's Disease Using Pharmacophore‐Based Virtual Screening

Abstract Glycogen synthase kinase‐3β (GSK‐3β) plays pivotal role in regulating diverse range of cellular functions. It plays negative role in cellular signaling pathways and believed to involved in the pathologies of various diseases like neurological disorders, type II diabetes, inflammation, cardiac hypertrophy, cancer and bipolar disorders. GSK‐3β is proposed as a promising target for drug discovery in treating these disease conditions. A number of structurally different chemical scaffolds including pyrimidinone derivatives have been identified as potential GSK‐3β inhibitors. In the current study, PHASE module of Schrödinger 3D QSAR was used on about 157 pyrimidinone derivatives for the development of statistically significant PLS model. Consecutively, the best pharmacophore hypothesis with features like three hydrogen bond acceptors (A1‐3), two hydrophobic regions (H1 and H2), and one aromatic ring (R1), was selected to screen ZINC and PUBCHEM databases. Molecules with matching pharmacophoric features and ROF were subjected to structure‐based virtual screening (HTVS→SP→XP) and MMGBSA. Two hits from each library were selected for MD simulation studies that showed good pharmacokinetic properties, binding score (−6.8–−8.8 kcal/mol) and ▵G MMGBSA (−55.80–−58.1 kcal/mol) as compared to the reference molecule, NP‐12. Similarly, MD simulation, and MMPBSA identified three compounds i. e. ZINC67743231, ZINC01582756, and PUBCHEM11553018 displaying stability in the binding pocket and demonstrated better binding affinity of −22.07, −27.33, and −30.61 kcal/mol, respectively, within the active site of GSK‐3β. DFT studies also demonstrated the stability of these three lead compounds with a high energy gap between HOMO and LUMO ranging between 0.14546 and 0.1718 eV.