scholarly journals Small molecules inhibiting Keap1–Nrf2 protein–protein interactions: a novel approach to activate Nrf2 function

MedChemComm ◽  
2017 ◽  
Vol 8 (2) ◽  
pp. 286-294 ◽  
Author(s):  
Chunlin Zhuang ◽  
Zhongli Wu ◽  
Chengguo Xing ◽  
Zhenyuan Miao
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Small Molecule Inhibition ◽  
Novel Approach ◽  
Nrf2 Protein

Small-molecule inhibition of Keap1–Nrf2 protein–protein interactions as a novel approach to activate Nrf2.

scholarly journals Small molecules that inhibit TNF signalling by stabilising an asymmetric form of the trimer

2019 ◽  
Vol 10 (1) ◽  
Author(s):  
James O’Connell ◽  
John Porter ◽  
Boris Kroeplien ◽  
Tim Norman ◽  
Stephen Rapecki ◽  
...  
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Protein Interactions ◽  
General Mechanism ◽  
Protein Protein Interactions ◽  
Biologic Drugs ◽  
Small Molecule Drugs ◽  
Necrosis Factor

AbstractTumour necrosis factor (TNF) is a cytokine belonging to a family of trimeric proteins; it has been shown to be a key mediator in autoimmune diseases such as rheumatoid arthritis and Crohn’s disease. While TNF is the target of several successful biologic drugs, attempts to design small molecule therapies directed to this cytokine have not led to approved products. Here we report the discovery of potent small molecule inhibitors of TNF that stabilise an asymmetrical form of the soluble TNF trimer, compromising signalling and inhibiting the functions of TNF in vitro and in vivo. This discovery paves the way for a class of small molecule drugs capable of modulating TNF function by stabilising a naturally sampled, receptor-incompetent conformation of TNF. Furthermore, this approach may prove to be a more general mechanism for inhibiting protein–protein interactions.

scholarly journals Regulation of cadherin dimerization by chemical fragments as a trigger to inhibit cell adhesion

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Akinobu Senoo ◽  
Sho Ito ◽  
Satoru Nagatoishi ◽  
Yutaro Saito ◽  
Go Ueno ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Hydrogen Bonds ◽  
Small Molecules ◽  
Small Molecule ◽  
Protein Interactions ◽  
Therapeutic Potential ◽  
Protein Complexes ◽  
Protein Protein Interactions ◽  
Specific Chemical ◽  
Stepwise Assembly

AbstractMany cadherin family proteins are associated with diseases such as cancer. Since cell adhesion requires homodimerization of cadherin molecules, a small-molecule regulator of dimerization would have therapeutic potential. Herein, we describe identification of a P-cadherin-specific chemical fragment that inhibits P-cadherin-mediated cell adhesion. Although the identified molecule is a fragment compound, it binds to a cavity of P-cadherin that has not previously been targeted, indirectly prevents formation of hydrogen bonds necessary for formation of an intermediate called the X dimer and thus modulates the process of X dimerization. Our findings will impact on a strategy for regulation of protein-protein interactions and stepwise assembly of protein complexes using small molecules.

scholarly journals Targeting epigenetic protein–protein interactions with small-molecule inhibitors

2020 ◽  
Vol 12 (14) ◽  
pp. 1305-1326 ◽  
Author(s):  
Brian M Linhares ◽  
Jolanta Grembecka ◽  
Tomasz Cierpicki
Keyword(s):  
Small Molecules ◽  
Small Molecule ◽  
Protein Interactions ◽  
Small Molecule Inhibitors ◽  
Chemical Space ◽  
Scaffolding Proteins ◽  
Protein Protein Interactions ◽  
Post Translational Modifications ◽  
Inhibitor Development ◽  
Interdisciplinary Approaches

Epigenetic protein–protein interactions (PPIs) play essential roles in regulating gene expression, and their dysregulations have been implicated in many diseases. These PPIs are comprised of reader domains recognizing post-translational modifications on histone proteins, and of scaffolding proteins that maintain integrities of epigenetic complexes. Targeting PPIs have become focuses for development of small-molecule inhibitors and anticancer therapeutics. Here we summarize efforts to develop small-molecule inhibitors targeting common epigenetic PPI domains. Potent small molecules have been reported for many domains, yet small domains that recognize methylated lysine side chains on histones are challenging in inhibitor development. We posit that the development of potent inhibitors for difficult-to-prosecute epigenetic PPIs may be achieved by interdisciplinary approaches and extensive explorations of chemical space.

A systematic molecular dynamics approach to the study of peptide Keap1–Nrf2 protein–protein interaction inhibitors and its application to p62 peptides

2016 ◽  
Vol 12 (4) ◽  
pp. 1378-1387 ◽  
Author(s):  
Meng-Chen Lu ◽  
Zhen-Wei Yuan ◽  
Yong-Lin Jiang ◽  
Zhi-Yun Chen ◽  
Qi-Dong You ◽  
...  
Keyword(s):  
Molecular Dynamics ◽  
Small Molecule ◽  
Protein Interaction ◽  
Protein Interactions ◽  
Drug Targets ◽  
Protein Protein Interactions ◽  
Protein Protein Interaction ◽  
P Protein ◽  
Nrf2 Protein

Protein–protein interactions (PPIs) as drug targets have been gaining growing interest, though developing drug-like small molecule PPI inhibitors remains challenging.

Small-molecule modulation of p53 protein-protein interactions

2020 ◽  
Vol 401 (8) ◽  
pp. 921-931 ◽  
Author(s):  
Ave Kuusk ◽  
Helen Boyd ◽  
Hongming Chen ◽  
Christian Ottmann
Keyword(s):  
Tumor Suppressor ◽  
Small Molecules ◽  
Small Molecule ◽  
Protein Interactions ◽  
P53 Protein ◽  
Tumor Suppressor Protein ◽  
Protein Protein Interactions ◽  
Mdm2 Protein ◽  
Protein Protein Interaction ◽  
Altered Proteins

AbstractSmall-molecule modulation of protein-protein interactions (PPIs) is a very promising but also challenging area in drug discovery. The tumor suppressor protein p53 is one of the most frequently altered proteins in human cancers, making it an attractive target in oncology. 14-3-3 proteins have been shown to bind to and positively regulate p53 activity by protecting it from MDM2-dependent degradation or activating its DNA binding affinity. PPIs can be modulated by inhibiting or stabilizing specific interactions by small molecules. Whereas inhibition has been widely explored by the pharmaceutical industry and academia, the opposite strategy of stabilizing PPIs still remains relatively underexploited. This is rather interesting considering the number of natural compounds like rapamycin, forskolin and fusicoccin that exert their activity by stabilizing specific PPIs. In this review, we give an overview of 14-3-3 interactions with p53, explain isoform specific stabilization of the tumor suppressor protein, explore the approach of stabilizing the 14-3-3σ-p53 complex and summarize some promising small molecules inhibiting the p53-MDM2 protein-protein interaction.

scholarly journals Protein–protein interactions as targets for small-molecule therapeutics in cancer

2008 ◽  
Vol 10 ◽  
Author(s):  
Alex W. White ◽  
Andrew D. Westwell ◽  
Ghali Brahemi
Keyword(s):  
Drug Design ◽  
Small Molecule ◽  
Protein Interactions ◽  
Therapeutic Potential ◽  
Drug Binding ◽  
Protein Protein Interactions ◽  
Small Molecule Inhibition ◽  
Conventional Drug ◽  
Initial Identification ◽  
Small Molecule Therapeutics

Small-molecule inhibition of the direct protein–protein interactions that mediate many important biological processes is an emerging and challenging area in drug design. Conventional drug design has mainly focused on the inhibition of a single protein, usually an enzyme or receptor, since these proteins often contain a clearly defined ligand-binding site with which a small-molecule drug can be designed to interact. Designing a small molecule to bind to a protein–protein interface and subsequently inhibit the interaction poses several challenges, including the initial identification of suitable protein–protein interactions, the surface area of the interface (it is often large), and the location of ‘hot spots’ (small regions suitable for drug binding). This article reviews the general approach to designing inhibitors of protein–protein interactions, and then focuses on recent advances in the use of small molecules targeted against a variety of protein–protein interactions that have therapeutic potential for cancer.

scholarly journals Targeting Chaperone/Co-Chaperone Interactions with Small Molecules: A Novel Approach to Tackle Neurodegenerative Diseases

Cells ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2596
Author(s):  
Lisha Wang ◽  
Liza Bergkvist ◽  
Rajnish Kumar ◽  
Bengt Winblad ◽  
Pavel F. Pavlov
Keyword(s):  
Neurodegenerative Diseases ◽  
Small Molecules ◽  
Protein Interactions ◽  
Intracellular Transport ◽  
Atp Hydrolysis ◽  
Specific Protein ◽  
Future Perspective ◽  
Protein Protein Interactions ◽  
Novel Approach ◽  
Chaperone Interactions

The dysfunction of the proteostasis network is a molecular hallmark of neurodegenerative diseases such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis. Molecular chaperones are a major component of the proteostasis network and maintain cellular homeostasis by folding client proteins, assisting with intracellular transport, and interfering with protein aggregation or degradation. Heat shock protein 70 kDa (Hsp70) and 90 kDa (Hsp90) are two of the most important chaperones whose functions are dependent on ATP hydrolysis and collaboration with their co-chaperones. Numerous studies implicate Hsp70, Hsp90, and their co-chaperones in neurodegenerative diseases. Targeting the specific protein–protein interactions between chaperones and their particular partner co-chaperones with small molecules provides an opportunity to specifically modulate Hsp70 or Hsp90 function for neurodegenerative diseases. Here, we review the roles of co-chaperones in Hsp70 or Hsp90 chaperone cycles, the impacts of co-chaperones in neurodegenerative diseases, and the development of small molecules modulating chaperone/co-chaperone interactions. We also provide a future perspective of drug development targeting chaperone/co-chaperone interactions for neurodegenerative diseases.

Elucidating Protein-protein Interactions Through Computational Approaches and Designing Small Molecule Inhibitors Against them for Various Diseases

2018 ◽  
Vol 18 (20) ◽  
pp. 1719-1736 ◽  
Author(s):  
Sharanya Sarkar ◽  
Khushboo Gulati ◽  
Manikyaprabhu Kairamkonda ◽  
Amit Mishra ◽  
Krishna Mohan Poluri
Keyword(s):  
Small Molecule ◽  
Protein Interactions ◽  
Small Molecule Inhibitors ◽  
Computational Techniques ◽  
Protein Protein Interactions ◽  
Computational Tools ◽  
Computational Approaches ◽  
Protein Protein Interaction ◽  
Wide Range ◽  
Therapeutic Measures

Background: To carry out wide range of cellular functionalities, proteins often associate with one or more proteins in a phenomenon known as Protein-Protein Interaction (PPI). Experimental and computational approaches were applied on PPIs in order to determine the interacting partners, and also to understand how an abnormality in such interactions can become the principle cause of a disease. Objective: This review aims to elucidate the case studies where PPIs involved in various human diseases have been proven or validated with computational techniques, and also to elucidate how small molecule inhibitors of PPIs have been designed computationally to act as effective therapeutic measures against certain diseases. Results: Computational techniques to predict PPIs are emerging rapidly in the modern day. They not only help in predicting new PPIs, but also generate outputs that substantiate the experimentally determined results. Moreover, computation has aided in the designing of novel inhibitor molecules disrupting the PPIs. Some of them are already being tested in the clinical trials. Conclusion: This review delineated the classification of computational tools that are essential to investigate PPIs. Furthermore, the review shed light on how indispensable computational tools have become in the field of medicine to analyze the interaction networks and to design novel inhibitors efficiently against dreadful diseases in a shorter time span.

scholarly journals Theoretical models of inhibitory activity for inhibitors of protein–protein interactions: targeting menin–mixed lineage leukemia with small molecules

MedChemComm ◽  
2017 ◽  
Vol 8 (12) ◽  
pp. 2216-2227 ◽  
Author(s):  
Wiktoria Jedwabny ◽  
Szymon Kłossowski ◽  
Trupta Purohit ◽  
Tomasz Cierpicki ◽  
Jolanta Grembecka ◽  
...  
Keyword(s):  
Small Molecules ◽  
Binding Affinity ◽  
Protein Interactions ◽  
Empirical Model ◽  
Inhibitory Activity ◽  
Theoretical Models ◽  
Mixed Lineage Leukemia ◽  
Protein Protein Interactions ◽  
Model Based ◽  
Dispersion Terms

A computationally affordable, non-empirical model based on electrostatic multipole and dispersion terms successfully predicts the binding affinity of inhibitors of menin–MLL protein–protein interactions.

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