Alzheimer's disease (AD) is the most common dementia in late life memory related issues. It is estimated that worldwide 46.8 million people suffer from dementia. The hypoxia inducible factor (HIF) upregulation could be a potential neuroprotective strategy by modulating the multiple survival pathways in AD. Hence, the development of small molecules that induce HIF-α activation via inhibition of prolyl hydroxylase enzyme (PHD) has been suggested as a potentially useful therapeutic strategy for the treatment of AD. Thus, to unveil a novel human PHD inhibitor, 2D-QSAR (Quantitative Structure Activity Relationship) modeling was performed with the 213 PHD inhibitors reported in the USA patent database. Best model with the r2 score of 0.8273 and q2 value of 0.8284 with dendritic fingerprint was developed and visualized by kernel partial least squares (KPLS) methods, which were used for visualization and screening of natural/derivative compounds database for novel and effective drug or scaffold. The docking was performed as a secondary strategy for screening the top 5000 compounds retrieved by 2D-QSAR based screening. Further, the docked complexes were screened by molecular dynamics (MD) simulation and molecular mechanics/generalized Born surface area (MM-GBSA) based binding free energy calculations to determine the binding energy of the inhibitors and to identify crucial interacting energy contributors. Three leads have demonstrated good binding free energy and the better binding affinity for PHD compared to other selected ligands. Thus, the results obtained from QSAR, docking and MD simulations depicted that hydantoin scaffold could be effectively used as a potent inhibitor toward human PHD in AD therapeutics.Communicated by Ramaswamy H. Sarma.
Keywords: AutoQSAR; MM-GBSA; Prolyl hydroxylase; RQSAR; docking; molecular dynamics.