Role of surface-exposed charged basic amino acids (Lys, Arg) and guanidination in insulin on the interaction and stability of insulin-insulin receptor complex.

Autor: Lee VS; Department of Chemistry, Drug Design Development Research Group, Center of Theoretical and Computational Physics (CTCP), Faculty of Science, University of Malaya, 50603, Kuala Lumpur, Malaysia. Electronic address: vannajan@um.edu.my., Sukumaran SD; Department of Chemistry, Drug Design Development Research Group, Center of Theoretical and Computational Physics (CTCP), Faculty of Science, University of Malaya, 50603, Kuala Lumpur, Malaysia., Tan PK; Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia., Kuppusamy UR; Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia., Arumugam B; Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia. Electronic address: bavani@um.edu.my.
Jazyk: angličtina
Zdroj: Computational biology and chemistry [Comput Biol Chem] 2021 Jun; Vol. 92, pp. 107501. Date of Electronic Publication: 2021 Apr 24.
DOI: 10.1016/j.compbiolchem.2021.107501
Abstrakt: 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 half-life, 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 = NHNH 2 ) enhanced and exerted stronger binding of the protein to its receptor through electrostatic interaction than native insulin (Lys-NH 3 + ). 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.
(Copyright © 2021. Published by Elsevier Ltd.)
Databáze: MEDLINE
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