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Allostery in Drug Development

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Protein Allostery in Drug Discovery

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1163))

Abstract

Allosteric regulation is a ubiquitous strategy employed in nature to control cellular processes by regulating the affinities of biomolecules. Allosteric modulators are able to tune the protein/substrate affinity in a highly predictable way, suggesting that such modulators may represent safe drugs. Tremendous advances have been made in the development of allosteric modulators and the characterization of their therapeutic targets. Here, we briefly introduce several representative allosteric modulators of important drug targets, such as the G protein-coupled receptor family. We also review the state-of-the-art experimental and computational approaches used in allosteric drug development. The accumulated knowledge of allosteric regulation and the technical progress made in drug development will lead to an explosion of promising allosteric drugs in the near future.

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Abbreviations

ASD:

AlloSteric Database

BRET:

Bioluminescence resonance energy transfer

cAMP:

Cyclic adenosine monophosphate

CCR5:

C-C chemokine receptor type 5

DAG:

Diacylglycerol

DNA:

Deoxyribonucleic acid

EC50:

Half maximum effect concentration

EF:

Bacillus anthracis adenylyl cyclase toxin

Emax:

Maximum effect concentration

FDA:

Food and Drug Administration

FRET:

Fluorescence resonance energy transfer

GDP:

Guanosine diphosphate

GFP:

Green fluorescent protein

GPCR:

G protein-coupled receptor

GRK:

G protein-coupled receptor kinase

GTP:

Guanosine-5′-triphosphate

HIV/AIDS:

Human immunodeficiency virus infection and acquired immune deficiency syndrome

IP3:

Inositol triphosphate

MD:

Molecular dynamics

MSA:

Multiple sequence alignment

NMA:

Normal mode analysis

NMR:

Nuclear magnetic resonance

RET:

Resonance energy transfer

RNA:

Ribonucleic acid

SCA:

Statistical coupling analysis

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  1. State Key Laboratory of Drug Research, Drug Discovery and Design Center, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China

    Xi Cheng & Hualiang Jiang

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  1. Xi Cheng
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  1. Department of Pathophysiology, Key Laboratory of Cell Differentiation and Apoptosis of Chinese Ministry of Education, Shanghai Jiao Tong University, School of Medicine, Shanghai, China

    Jian Zhang

  2. Cancer and Inflammation Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, National Cancer Institute, Frederick, MD, USA, Sackler Institute of Molecular Medicine, Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Ruth Nussinov

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Cheng, X., Jiang, H. (2019). Allostery in Drug Development. In: Zhang, J., Nussinov, R. (eds) Protein Allostery in Drug Discovery. Advances in Experimental Medicine and Biology, vol 1163. Springer, Singapore. https://doi.org/10.1007/978-981-13-8719-7_1

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