Molecular Docking, Dynamics, and WaterSwap Analysis to Identify Anti-aggregating Agents of Insulin and IFN-β

There are several challenges in the development, and formulation of biologics, particularly concerning their physical stabilities. The self-assembly of peptides like human insulin and interferon beta (IFN-β) has potential to form aggregates in pharmaceutical formulation. Therefore, it is a significant problem in the manufacturing, storage, and delivery of insulin and IFN-β formulations. Amino acids as aggregation suppressing additives have been used to stabilize proteins during manufacturing and storage. Several changes to the B chain’s C-terminus have been proposed in an attempt to improve insulin formulation. The core segments of the A and B chains (SLYQLENY and LVEALYLV) have recently been identified as sheet-forming areas, and their microcrystalline structures have been exploited to construct a high-resolution insulin amyloid fibril model. Here, we have chosen twenty-one amino acids to develop as additives in rendering the insulin and IFN-β aggregations. Thereafter, integrated molecular docking studies of single layer monomers of full-length insulin and IFN-β have been performed to identify structural elements (amino acids) that can act as disaggregating agents. The stability of the best-docked amino acid complexes was judged using molecular dynamics studies. Finally, phenylalanine was identified as a disaggregation agent for insulin, and lysine, tyrosine, phenylalanine, and tryptophan were identified as disaggregation agents for IFN-β from the molecular dynamics study. These findings may open a novel proposal to explore further in vitro studies to increase the stability of the insulin and IFN-β formulation. Graphical Abstract