Computational elucidation of allosteric communication in proteins for allosteric drug design

Duan Ni; Yaqin Liu; Ren Kong; Zhengtian Yu; Shaoyong Lu; Jian Zhang

doi:10.1016/j.drudis.2022.03.012

Computational elucidation of allosteric communication in proteins for allosteric drug design

Drug Discov Today. 2022 Aug;27(8):2226-2234. doi: 10.1016/j.drudis.2022.03.012. Epub 2022 Mar 18.

Authors

Duan Ni¹, Yaqin Liu², Ren Kong³, Zhengtian Yu⁴, Shaoyong Lu⁵, Jian Zhang⁶

Affiliations

¹ College of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, China; State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China; The Charles Perkins Centre, University of Sydney, Sydney, NSW 2006, Australia.
² Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China.
³ Institute of Bioinformatics and Medical Engineering, School of Electrical and Information Engineering, Jiangsu University of Technology, Changzhou 213001, China.
⁴ Nutshell Therapeutics, Shanghai 201203, China.
⁵ College of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, China; State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China; Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China. Electronic address: lushaoyong@sjtu.edu.cn.
⁶ College of Pharmacy, Ningxia Medical University, Yinchuan, Ningxia Hui Autonomous Region 750004, China; State Key Laboratory of Oncogenes and Related Genes, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China; Medicinal Chemistry and Bioinformatics Center, Shanghai Jiao Tong University, School of Medicine, Shanghai 200025, China; School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450001, China. Electronic address: jian.zhang@sjtu.edu.cn.

PMID: 35314339
DOI: 10.1016/j.drudis.2022.03.012

Abstract

Allosteric modulators target topologically distal allosteric sites in order to modulate orthosteric sites, providing enhanced specificity and physiochemical properties. Harnessing allostery for drug discovery is an emerging paradigm in modern pharmaceutics. Allosteric regulation substantially depends on the propagation of allosteric signaling. Delineating allosteric signaling pathways is therefore one of the leading prerequisites for allosteric drug discovery. Allosteric signal transduction is subtle and dynamic, posing challenges for characterization through traditional experimental techniques, but computational strategies promise to provide a solution to this problem. Here, we comprehensively review bioinformatic methods for elucidating allosteric communication, along with their successful applications in allosteric drug design. Current challenges and future perspectives are also discussed. We aim to provide guidance for the future application and optimization of these computational strategies, thereby promoting rational allosteric drug discovery.

Keywords: Allosteric communication; Allosteric drug; Allosteric regulation; Allostery; Computational methods.

Publication types

Review
Research Support, Non-U.S. Gov't

MeSH terms

Allosteric Regulation
Allosteric Site
Communication
Drug Design*
Ligands
Proteins* / metabolism

Substances

Ligands
Proteins