In silico designing of activator for human IGF2 protein for effective cardiovascular disease therapeutics

AbstractInsulin like growth factor-II (IGF2) is a member of IGF family, the main role of IGF2 is as a growth hormone during gestation or fetal development. Ischematic stroke, atherosclerosis and pathological cardiac hypertrophy are associated with low circulating levels of IGF2. 5-aza-2’-deoxycytidine increases the activity of IGF2, due to high toxicity of 5aza2’deoxycytidine, some silenced genes are also expressed that cause various cancer diseases. In the present study an in silico approach was used to design the potential activator for IGF2 without side effects to treat cardiovascular diseases. Ligand binding sites were predicted using CASTp for drug target. 361 ligand analogs for 5-aza-2’-deoxycytidine were identified through virtual screening from Ligand.Info database. Docking studies were performed using Schrodinger software (2010) generated 13 lead agonists for human IGF2. Docking complexes of 13 lead agonists and 5aza2’deoxycytidine with IGF2 were compared and four leads with better affinity, ADME properties and lower XPGscore than 5-aza-2’-deoxycytidine were proposed as potential activators. Lead‘1’ (mizoribine), the best ranked activator (XPG score -7.181) having good binding affinity, could be a better drug for cardiovascular diseases and it is forming three hydrogen bonds, two bonds with Thr-58 and one bond with Cys-60, and van der Waal interactions with the binding site residues of IGF2 such as Leu-13, Leu-17 Ile-42, Val-43, Cys-46, Leu-56 and Try -59. Mizoribine decreases the proliferation of vascular smooth muscle cells and the elevated levels of human IGF2 helps in cardiovascular therapies.