Homology modeling and molecular docking studies for the identification of novel potential therapeutics against human PHD3 as a drug target for type 2 diabetes mellitus
PHD3 (Prolyl Hydroxylating Domain) 3 protein contains the HRE (Hypoxia Response Element) and plays an important role in regulating HIF subunits. The hydroxylating ability of PHD3 of HIF subunits makes PHD3 is a prominent therapeutic target to control type 2 diabetes mellitus. The structure based approach is used to design novel molecular entities against PHD3 protein. In this present work, a 3D homology model of PHD3 was generated by MODELLER9.9 as the experimental structure of PHD3 is not reported in the protein database. The 3d structural model of PHD3 refined through energy minimization in VMD-NAMD interface. Active site of the target protein is identified by SiteMap module (Schrodinger suite), manual correlation technique using ClustalW software and literature studies. The asinex library of chemical structures subjected to the molecular docking at the PHD3 active site for the identification of potent inhibitors. The molecules resulted from molecular docking prioritized based on their docking score, glide energy. The ligand molecules are further prioritized with a rescoring parameter Prime-MM/GBSA by calculating binding free energies of final Ligand-Protein complexes. The identified novel leads are further evaluated with ADME properties for their druglikeness activity. The overall insights can further expedite for the development of novel molecular entities as potential inhibitors against PHD3 in type 2 diabetes mellitus.
Keywords: PHD3, homology model, VMD-NAMD, Prime-MM/GBSA, ADME, type 2 diabetes mellitus.
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