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In silico identification of prolyl hydroxylase inhibitor by per‐residue energy decomposition‐based pharmacophore approach

Hypoxia is an effective preconditioning stimulus and many cellular responses to hypoxia are mediated through a transcription control complex termed the hypoxia‐inducible factor (HIF). The stability and activation of HIF are governed by HIF prolyl‐4‐hydroxylases 2 (PHD2). Hence, the development of a small molecule inhibitor for prolyl hydroxylase has been suggested as a potentially useful therapeutic strategy for the treatment of oxidative/ischemic stress conditions. Thus, to unveil a novel human PHD2 inhibitor, a custom‐based virtual screening was carried out to identify the potential inhibitors against PHD2 based on; (1) the per‐residue energy decomposition (PRED)‐based pharmacophore model, (2) molecular docking, and (3) MD approaches. The PRED analysis was performed to identify the common interaction pattern of HIF fragment (5L9B) and crystallized ligand (4JZR) to develop a relevant accurate allosteric pharmacophore model. The custom pharmacophore model (AAARR) was developed and further used to screen multiple databases. The docking was performed as a secondary strategy for screening the pharmacophore hits. Furthermore, 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 interaction energy fingerprint. One hit has demonstrated good binding free energy and a better binding affinity for PHD2 compared to the other four selected ligands. Thus, the results obtained from pharmacophore, docking, and MD simulations depicted that linker length and metal binding in the scaffold could be effectively used as a potent inhibitor toward human PHD2 in AD therapeutics.