Abstract
Purpose: To identify the structural requirements for designing a lead key for insulin-like growth factor (IGF-1R) inhibition using group-based quantitative structure activity relationship (GQSAR) and molecular docking.Methods: GQSAR method requires fragmentation of molecules. The molecules in the current dataset were fragmented into three (R1, R2 and R3) by applying common fragmentation pattern, and fragmentbased 2D descriptors were then calculated. GQSAR models were derived by applying various methods including multiple linear regressions and partial least square or k-nearest neighbour.Results: Four generated GQSAR models were selected based on the statistical significance of the model. It was found that the presence of flexible and non-aromatic groups on fragment R1 was conducive for inhibition. Additionally, the existence of amino groups as hydrogen bond donors at fragments R2 and R3 was fruitful for inhibition. Docking studies revealed the binding orientation adopted by the active compounds at several amino acid residues, including Met 1126, Arg, 1128, Met 1052, GLU 1050, Met 1112, Leu 1051, Met 1049, Val 1033, and Val 983 at ATP binding sites of IGF-1R kinase domain.Conclusion: The generated models provide a site-specific insight into the structural requirements for IGF-1R inhibition which can be used to design and develop potent inhibitors.Keywords: Insulin-like growth factor 1 (IGF-1) receptor, Quantitative structure-activity relationship, Adenosine triphosphate, Competitive inhibitors, Electrotopological state index.
Highlights
Insulin-like growth factor-1 receptor (IGF-1R) is a tyrosine kinase of the insulin receptor family with hetero-tetrameric α2β2 subunits
The biological activity of these ligands depends on the interactions with certain residues in the ATP binding sites of IGF-1R kinase domain, which serve as hydrogen bond donors, acceptors, or hydrophobic pockets
In addition to group-based quantitative structure activity relationship (GQSAR) analysis of the generated compounds, we explored the use of High throughput virtual screening (HTVS) and extraprecision (XP) docking to compare the binding mode as well as docking scores of the highly active BMS1112 and poorly active compounds BMS1605 in comparison to the native ligand BMS_754805 in the 3I81 crystal structure
Summary
Insulin-like growth factor-1 receptor (IGF-1R) is a tyrosine kinase of the insulin receptor family with hetero-tetrameric α2β2 subunits. Alpha subunit is located extracellularly and contains the binding domain, while the β subunit is mainly intracellular with a small portion spanning across the membranes. The latter subunits are responsible for intracellular signal transduction due to tyrosine kinase domain and associated motifs [1]. Physiological activation of IGF-1R, which activates PI3K/Akt/mTOR, and Ras/Raf/MEK/ ERK pathways only occurs upon binding of IGF-1 or IGF-2 ligands to the receptor. Ligand-dependent activation of IGF-1R is bypassed in many solid and hematological cancers leading to continuous activation of PI3K/Akt/mTOR and Ras/Raf/MEK/ERK pathways that promote proliferation and inhibition of apoptosis [3]. Despite the success in the design of IGF-1R inhibitors, there is a need to optimize the lead compounds to efficient drug compounds
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