Pharmacophore-based virtual screening of the chromone derivatives as potential therapeutic for Alzheimer’s disease

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Alzheimer’s disease is one of the most complex neurological disorders and millions of people are suffering from this disease all over the world. In the past two decades acetylcholinesterase (AChE) has been the most explored pathological hallmark. The generation of potent AChE inhibitors has grown as a rapid pathological tool for the efficacious treatment of the disease. Hence, AChE enzyme is extensively explored as a drug discovery tool for the development of potent therapeutics. We have used chromone derivatives with known biological activities for developing a Gaussian field-based 3D QSAR pharmacophore model using PHASE module of Schrodinger with statistically significant R2 and Q2 values of 0.92 and 0.9209, respectively. ChEMBL and MCULE databases were screened using the best pharmacophore hypothesis model (AAHHRR_4) with features of two hydrogen bond acceptors (A1, A2), two hydrophobic regions (H1, H2), and two aromatic regions (R1, R2). These were subjected to structure-based virtual screening using extra precision, MM/GBSA and ADME calculations for calculating the binding free energies and pharmacokinetic properties, respectively. Subsequently, two hit molecules i.e. CHEMBL1319989 and MCULE-2246633290 were identified. The leads exhibited higher docking score (−8.859 and −9.984 kcal/mol) and ΔGbinding (−57.63 and −56.45 kcal/mol) as compared to the reference (ΔGbinding= −53.79 kcal/mol). MD simulation study exhibited stable interactions with the binding free energy (ΔGMMPBSA) of −27.29 and −21.26 kcal/mol for CHEMBL1319989 and MCULE-2246633290, respectively. So, the generated pharmacophore model may be considered as a valuable tool for the development of potent AChE inhibitors for the treatment of AD.