Lee, Vannajan Sanghiran and Sukumaran, Sri Devi and Kheong, Tan Pak and Kuppusamy, Umah Rani and Arumugam, Bavani (2021) Role of surface-exposed charged basic amino acids (Lys, Arg) and guanidination in insulin on the interaction and stability of insulin-insulin receptor complex. Computational Biology And Chemistry, 92. ISSN 1476-9271, DOI https://doi.org/10.1016/j.compbiolchem.2021.107501.
Full text not available from this repository.Abstract
Naturally occurring proteins are emerging as novel therapeutics in the protein-based biopharmaceutical industry for the treatment of diabetes and obesity. However, proteins are not suitable for oral delivery due to short halflife, reduced physical and chemical stability and low permeability across the membrane. Chemical modification has been identified as a formulation strategy to enhance the stability and bioavailability of protein drugs. The present study aims to study the effect of charge-specific modification of basic amino acids (Lys, Arg) and guanidination on the interaction of insulin with its receptor using molecular modelling. Our investigation revealed that the guanidination of insulin (Lys-NHC = NHNH2) enhanced and exerted stronger binding of the protein to its receptor through electrostatic interaction than native insulin (Lys-NH3+). Point mutations of Lys and Arg (R22, K29; R22K, K29; R22, K29R; R22K, K29R) were attempted and the effects on the interaction and stability between insulin/modified insulins and insulin receptor were also analyzed in this study. The findings from the study are expected to provide a better understanding of the possible mechanism of action of the modified protein at a molecular level before advancing to real experiments.
| Item Type: | Article |
|---|---|
| Funders: | Ministry of Education Malaysia (Fundamental Research Grant Scheme) (FP0362017A), University of Malaya, Malaysia (University Malaya Research Grant) (RG396-17AFR), University of Malaya, Malaysia (Faculty Research Grant) (GPF063B2018) |
| Uncontrolled Keywords: | Guanidination; Insulin; Insulin receptor; Tyrosine kinase receptor |
| Subjects: | Q Science > QD Chemistry R Medicine > R Medicine (General) |
| Divisions: | Faculty of Medicine Faculty of Science > Department of Chemistry |
| Depositing User: | Ms Zaharah Ramly |
| Date Deposited: | 21 Jul 2022 03:54 |
| Last Modified: | 21 Jul 2022 03:54 |
| URI: | http://eprints.um.edu.my/id/eprint/28083 |
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