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

Author:

Alizadeh Ali A.1ORCID,Dastmalchi Siavoush1ORCID

Affiliation:

1. Biotechnology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran

Abstract

Introduction: Short bowel syndrome (SBS) is a disabling condition which occurs following the loss of substantial portions of intestine leading to inadequate absorption of nutrients and fluids. Teduglutide is the only drug which 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. Result: 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.

Funder

National Institute for Medical Research Development

Publisher

Bentham Science Publishers Ltd.

Subject

Drug Discovery,Molecular Medicine,General Medicine

Cited by 2 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3