Protein-protein interaction modulators: advances, successes and remaining challenges

  • Lloyd Mabonga
  • Abidemi Paul KappoEmail author


Modulating disease-relevant protein-protein interactions (PPIs) using small-molecule inhibitors is a quite indispensable diagnostic and therapeutic strategy in averting pathophysiological cues and disease progression. Over the years, targeting intracellular PPIs as drug design targets has been a challenging task owing to their highly dynamic and expansive interfacial areas (flat, featureless and relatively large). However, advances in PPI-focused drug discovery technology have been reported and a few drugs are already on the market, with some potential drug-like candidates already in clinical trials. In this article, we review the advances, successes and remaining challenges in the application of small molecules as valuable PPI modulators in disease diagnosis and therapeutics.


Protein-protein interactions Small molecules Modulators Drug-like Macrocycles Small-molecule inhibitors 



Protein-protein interactions




Interleukin-2 receptor alpha chain


Fragment-based drug discovery


Fragment-based lead discovery


Structure-activity relationship


Nuclear magnetic resonance


B cell lymphoma 2


B cell lymphoma-extra large


Computational solvent


Mouse double minute 2 homolog


Human papillomavirus


Tumour necrosis factor


Tumour necrosis factor alpha


Tumour necrosis factor receptor 1


Filamenting temperature-sensitive mutant Z


Z interacting protein A


High-throughput screening


Core binding factor


Diversity-oriented synthesis


Sonic Hedgehog


Protein phosphatase 2C homolog 1


Mammalian target of rapamycin


FK-binding protein 12


DNA-programmed chemistry


Signal transducers and activators of transcription


Monoclonal antibody


Human epidermal growth factor receptor 2


Intercellular adhesion molecule-1


Vascular endothelial growth factor


Granulocyte colony-stimulating factor




Leukocyte integrin lymphocyte function-associated antigen 1


G protein-coupled receptor


C-C chemokine receptor type 5


C-X-C chemokine receptor type 4


C-X-C chemokine receptor type 7


Multiple myeloma


B cell chronic lymphocytic leukaemia


Adenomatous polyposis coli


Glycogen synthase kinase 3


T cell factor


Diffuse large B cell lymphoma


B cell lymphoma 6


Silencing mediator for retinoid or thyroid-hormone receptors


Histone deacetylase 3


Checkpoint kinase 1


Cyclin-dependent kinase inhibitor 1


Ataxia telangiectasia and Rad3-related protein


Computer-aided drug design


A-kinase anchoring protein


Cyclic adenosine monophosphate




Ubiquitin proteasome system


Ubiquitin-proteasome pathway


Cullin RING E3 ligase


Inhibition constant


TNF-related apoptosis-inducing ligand


Small cell lung cancer


Pancreatic acinar cells


Stabilised alpha-helix of Bcl-2 domains


T cell acute lymphoblastic leukaemia


A disintegrin and metalloproteinase


Intracellular domain of NOTCH1




Dominant-negative fragment of MAML1



Abidemi Paul Kappo is thankful to the National Research Foundation (NRF), South Africa for a Thuthuka Grant (Grant No: 107262) award and University of Zululand Research Committee for their support. Llyod Mabonga is thankful to the Department of Science and Technology (DST) and the NRF for a Doctoral Research Bursary. The contents of this manuscript are solely the responsibility of the authors and do not necessarily represent the official views of the DST, NRF and the University of Zululand.

Compliance with ethical standards

Conflict of interest

Lloyd Mabonga declares that he has no conflict of interest. Abidemi Paul Kappo declares that he has no conflict of interest.

Ethical approval

The article does not contain any studies with human participants or animals hence do not require ethics approval by the authors.


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Copyright information

© International Union for Pure and Applied Biophysics (IUPAB) and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Biotechnology and Structural Biology (BSB) Group, Department of Biochemistry and MicrobiologyUniversity of ZululandKwaDlangezwaSouth Africa

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