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Allosteric Modulators of Protein–Protein Interactions (PPIs)

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Protein Allostery in Drug Discovery

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

Abstract

Protein–protein interactions (PPIs) represent promising drug targets of broad-spectrum therapeutic interests due to their critical implications in both health and disease circumstances. Hence, they are widely accepted as the Holy Grail of drug development. Historically, PPIs were rendered “undruggable” for their large, flat, and pocket-less structures. Current attempts to drug these “intractable” targets include orthosteric and allosteric methodologies. Previous efforts employing orthosteric approaches like protein therapeutics and orthosteric small molecules frequently suffered from poor performance caused by the difficulties in directly targeting PPI interfaces. As structural biology progresses rapidly, allosteric modulators, which direct to the allosteric regulatory sites remote to the PPI surfaces, have gradually established as a potential solution. Allosteric pockets are topologically distal from the PPI orthosteric sites, and their ligands do not need to compete with the PPI partners, which helps to improve the physiochemical and pharmacological properties of allosteric PPI modulators. Thus, exploiting allostery to tailor PPIs is regarded as a tempting strategy in future PPI drug discovery. Here, we provide a comprehensive review of our representative achievements along the way we utilize allosteric effects to tame the difficult PPI systems into druggable targets. Importantly, we provide an in-depth mechanistic analysis of this success, which will be instructive to future related lead optimizations and drug design. Finally, we discuss the current challenges in allosteric PPI drug discovery. Their solutions as well as future perspectives are also presented.

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Authors and Affiliations

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

    Duan Ni

  2. School of Pharmacy, Second Military Medical University, Shanghai, China

    Na Liu & Chunquan Sheng

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  1. Duan Ni
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  2. Na Liu
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  3. Chunquan Sheng
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Correspondence to Chunquan Sheng .

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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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Ni, D., Liu, N., Sheng, C. (2019). Allosteric Modulators of Protein–Protein Interactions (PPIs). 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_13

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