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Current Computer-Aided Drug Design

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ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

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Research Article

Designing Novel Teduglutide Analogues with Improved Binding Affinity: An In Silico Peptide Engineering Approach

Author(s): Ali A. Alizadeh and Siavoush Dastmalchi*

Volume 17, Issue 2, 2021

Published on: 17 February, 2020

Page: [225 - 234] Pages: 10

DOI: 10.2174/1573409916666200217091456

Price: $65

Abstract

Introduction: Short bowel syndrome (SBS) is a disabling condition that occurs following the loss of substantial portions of the intestine, leading to inadequate absorption of nutrients and fluids. Teduglutide is the only drug that has been FDA-approved for long-term treatment of SBS. This medicine exerts its biological effects through binding to the GLP-2 receptor.

Methods: The current study aimed to use computational mutagenesis approaches to design novel potent analogues of teduglutide. To this end, the constructed teduglutide-GLP2R 3D model was subjected to the alanine scanning mutagenesis where ARG20, PHE22, ILE23, LEU26, ILE27 and LYS30 were identified as the key amino acids involved in ligand-receptor interaction. In order to design potent teduglutide analogues, using MAESTROweb machine learning method, the residues of teduglutide were virtually mutated into all naturally occurring amino acids and the affinity improving mutations were selected for further analysis using PDBePISA methodology which interactively investigates the interactions established at the interfaces of macromolecules.

Results: The calculations resulted in D15I, D15L, D15M and N24M mutations, which can improve the binding ability of the ligand to the receptor. The final evaluation of identified mutations was performed by molecular dynamics simulations, indicating that D15I and D15M are the most reliable mutations to increase teduglutide affinity towards its receptor.

Conclusion: The findings in the current study may facilitate designing more potent teduglutide analogues leading to the development of novel treatments in short bowel syndrome.

Keywords: Teduglutide, GLP-2, molecular modeling, molecular dynamics simulations, virtual alanine scanning, peptide design.

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