Study on the Electronic Structure of Insulin and its Analogues bound to IGF-1 Receptor by Canonical Molecular Orbital Method

Abstract

Insulin analogues, developed to improve glycemic control, have raised concerns regarding their potential carcinogenicity due to increased affinities for insulin-like growth factor-1 receptor (IGF-1R). The influences of mutations introduced in analogues still remain unknown, which make it challenging to definitively confirm or rule out the cancer risks associated with the use of insulin analogues. In this study, canonical molecular orbital (CMO) calculations of single structures of insulin analogues, and complex structure with L1 domain from IGF-1R were carried out. The results suggested that the mutated residues greatly altered the electronic structure of insulin, and their interactions with AspL38 from L1 domain might account for the varied affinity. Besides, residues playing crucial roles in interactions with L1 domain of IGF-1R were identified, offering guides for the design of insulin analogues.