Identification of new leads for human IGFBP-2: a therapeutic target for cardiovascular diseases

Abstract

AbstractIGFBP-2, the largest member of insulin-like growth factor binding proteins family, is under-expressed in hazardous cardiovascular diseases like obesity and type II diabetes mellitus, which upon aging leads to heart stroke. Therefore, IGFBP-2 has been proposed as a possible target for the development of novel leads for cardiovascular disease therapy. High-throughput virtual screening, one of the most common methods used to identify lead compounds was implemented here to identify potential IGFBP-2 activators. The NMR (nuclear magnetic resonance) structure of human IGFBP-2 was retrieved from the protein data bank. A 2D similarity search was performed for known IGFBP-2 activator TPA to acquire 383 structural analogs. The 3D structural conversion and multiple confirmations for 383 compounds were generated using LigPrep with ADME constraints. The docking and scoring calculations were performed using Glide v5.7. The extra precision (XP) docking reported 35 leads and ranked based on XP Gscore. Eleven leads having better XP Gscore compared to TPA were proposed as potential IGFBP-2 activators. Lead ’1’ (3,11-dihydroxyl-13-methyl-6,7,8,9,11,12,13,14,15,16-decahydro-cyclopenta [a] phenon) showed highest XP Gscore of -7.239 kcal/mol, good pharmacological properties and similar molecular interaction as TPA with IGFBP-2. Therefore, lead 1 was proposed as a promising lead of IGFBP-2 for the development of cardiovascular disease therapeutics.