Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Computational Screening and Experimental Validation of Inhibitor Targeting the Complex Formation of Grb14 and Insulin Receptor

Yosuke Ochi
,
Takanori Matsui
ORCID logo ,
Keitaro Inoue
,
Kohei Monobe
,
Hiroshi Sakamoto
,
Shunsuke Aoki
,
Junichi Taira
* ORCID logo
Version 1 : Received: 8 December 2023 / Approved: 8 December 2023 / Online: 8 December 2023 (08:24:15 CET)

A peer-reviewed article of this Preprint also exists.

Ochi, Y.; Matsui, T.; Inoue, K.; Monobe, K.; Sakamoto, H.; Aoki, S.; Taira, J. Computational Screening and Experimental Validation of Inhibitor Targeting the Complex Formation of Grb14 and Insulin Receptor. Molecules 2024, 29, 198. Ochi, Y.; Matsui, T.; Inoue, K.; Monobe, K.; Sakamoto, H.; Aoki, S.; Taira, J. Computational Screening and Experimental Validation of Inhibitor Targeting the Complex Formation of Grb14 and Insulin Receptor. Molecules 2024, 29, 198.

Abstract

The expedited development of drugs targeting gene products associated with insulin resistance holds the potential to enhance our comprehension of type 2 diabetes mellitus (T2DM). The virtual screening based on a three-dimensional (3D) protein structure has been expected as potential technique to accelerate a development of molecular target drugs. Among the targets implicated in insulin resistance, genetic characterization and protein function of Grb14 have been clarified without contradiction. The Grb14 gene displays notable variations in T2DM, and its gene product known to inhibit the function of the insulin receptor (IR) by directly binding to the tyrosine kinase domain. In the present study, a virtual screening, based on 3D structure of IR tyrosine kinase domain (IRβ) in complex with part of Grb14, was conducted to find compounds that can disrupt the complex formation between Grb14 and IRβ. First, ten compounds were selected from 154,118 compounds via hierarchical in silico structure-based drug screening, composed of grid docking-based and genetic algorithm-based programs. The experimental validations suggested that the one compound can affect blood glucose level. The molecular dynamics simulations and co-immunoprecipitation analysis showed that the compound did not completely suppress the protein–protein interaction between Grb14 and IR, though competitively bound to IR with the tyrosine kinase pseudosubstrate region in Grb14.

Keywords

DOCK program; GOLD program; Grb14; insulin receptor (IR); structure-based drug screening (SBDS)

Subject

Biology and Life Sciences, Biochemistry and Molecular Biology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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