Influence of Amino Acid Mutations and Small Molecules on Targeted Inhibition of Proteins Involved in Cancer

2019 ◽  
Vol 19 (6) ◽  
pp. 457-466 ◽  
Author(s):  
V. Kanakaveti ◽  
P. Anoosha ◽  
R. Sakthivel ◽  
S.K. Rayala ◽  
M.M. Gromiha
Keyword(s):  
Amino Acid ◽  
Small Molecules ◽  
Protein Interactions ◽  
Chemical Space ◽  
Clinical Success ◽  
Growth Factor Receptor ◽  
Protein Protein Interactions ◽  
Functional Aspects ◽  
Amino Acid Mutations ◽  
Targeted Inhibition

Background:Protein-protein interactions (PPIs) are of crucial importance in regulating the biological processes of cells both in normal and diseased conditions. Significant progress has been made in targeting PPIs using small molecules and achieved promising results. However, PPI drug discovery should be further accelerated with better understanding of chemical space along with various functional aspects.Objective:In this review, we focus on the advancements in computational research for targeted inhibition of protein-protein interactions involved in cancer.Methods:Here, we mainly focused on two aspects: (i) understanding the key roles of amino acid mutations in epidermal growth factor receptor (EGFR) as well as mutation-specific inhibitors and (ii) design of small molecule inhibitors for Bcl-2 to disrupt PPIs.Results:The paradigm of PPI inhibition to date reflect the certainty that inclination towards novel and versatile strategies enormously dictate the success of PPI inhibition. As the chemical space highly differs from the normal drug like compounds the lead optimization process has to be given the utmost priority to ensure the clinical success. Here, we provided a broader perspective on effect of mutations in oncogene EGFR connected to Bcl-2 PPIs and focused on the potential challenges.Conclusion:Understanding and bridging mutations and altered PPIs will provide insights into the alarming signals leading to massive malfunctioning of a biological system in various diseases. Finding rational elucidations from a pharmaceutical stand point will presumably broaden the horizons in future.

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.

scholarly journals SAAMBE-3D: Predicting Effect of Mutations on Protein–Protein Interactions

2020 ◽  
Vol 21 (7) ◽  
pp. 2563 ◽  
Author(s):  
Swagata Pahari ◽  
Gen Li ◽  
Adithya Krishna Murthy ◽  
Siqi Liang ◽  
Robert Fragoza ◽  
...  
Keyword(s):  
Amino Acid ◽  
Protein Interactions ◽  
Binding Free Energy ◽  
Pearson Correlation ◽  
Normal Function ◽  
Protein Protein Interactions ◽  
Cornell University ◽  
Genome Wide ◽  
New Development ◽  
Amino Acid Mutations

Maintaining wild type protein–protein interactions is essential for the normal function of cell and any mutation that alter their characteristics can cause disease. Therefore, the ability to correctly and quickly predict the effect of amino acid mutations is crucial for understanding disease effects and to be able to carry out genome-wide studies. Here, we report a new development of the SAAMBE method, SAAMBE-3D, which is a machine learning-based approach, resulting in accurate predictions and is extremely fast. It achieves the Pearson correlation coefficient ranging from 0.78 to 0.82 depending on the training protocol in benchmarking five-fold validation test against the SKEMPI v2.0 database and outperforms currently existing algorithms on various blind-tests. Furthermore, optimized and tested via five-fold cross-validation on the Cornell University dataset, the SAAMBE-3D achieves AUC of 1.0 and 0.96 on a homo and hereto-dimer test datasets. Another important feature of SAAMBE-3D is that it is very fast, it takes less than a fraction of a second to complete a prediction. SAAMBE-3D is available as a web server and as well as a stand-alone code, the last one being another important feature allowing other researchers to directly download the code and run it on their local computer. Combined all together, SAAMBE-3D is an accurate and fast software applicable for genome-wide studies to assess the effect of amino acid mutations on protein–protein interactions. The webserver and the stand-alone codes (SAAMBE-3D for predicting the change of binding free energy and SAAMBE-3D-DN for predicting if the mutation is disruptive or non-disruptive) are available.

scholarly journals Rebuilding Ring-Type Assembly of Peroxiredoxin by Chemical Modification

2020 ◽  
Author(s):  
Tomoki Himiyama ◽  
Yuko Tsuchiya ◽  
Yasushige Yonezawa ◽  
Tsutomu Nakamura
Keyword(s):  
Amino Acid ◽  
Protein Interactions ◽  
Hot Spots ◽  
Quaternary Structure ◽  
Protein Assembly ◽  
Protein Protein Interactions ◽  
Aeropyrum Pernix ◽  
Amino Acid Mutations ◽  
Regulate Protein ◽  
Additional Amino Acid

Direct control of protein quaternary structure (QS) is challenging owing to the complexity of protein structure. As a protein with a characteristic QS, peroxiredoxin from <i>Aeropyrum pernix</i> K1 (ApPrx) forms a decamer, wherein five dimers associate to form a ring. Here, we disrupted and reconstituted ApPrx QS via amino acid mutations and chemical modifications targeting hot spots for protein assembly. The decameric QS of an ApPrx* mutant, wherein all cysteine residues in wild-type ApPrx were mutated to serine, was destructed to dimers via an F80C mutation. The dimeric ApPrx*F80C mutant was then modified with a small molecule and successfully assembled as a decamer. Structural analysis confirmed that an artificially installed chemical moiety potentially facilitates suitable protein-protein interactions to rebuild a native structure. Rebuilding of dodecamer was also achieved through an additional amino acid mutation. This study describes a facile method to regulate protein assembly state.

scholarly journals Rebuilding Ring-Type Assembly of Peroxiredoxin by Chemical Modification

2020 ◽  
Author(s):  
Tomoki Himiyama ◽  
Yuko Tsuchiya ◽  
Yasushige Yonezawa ◽  
Tsutomu Nakamura
Keyword(s):  
Amino Acid ◽  
Protein Interactions ◽  
Hot Spots ◽  
Quaternary Structure ◽  
Protein Assembly ◽  
Protein Protein Interactions ◽  
Aeropyrum Pernix ◽  
Amino Acid Mutations ◽  
Regulate Protein ◽  
Additional Amino Acid

Direct control of protein quaternary structure (QS) is challenging owing to the complexity of protein structure. As a protein with a characteristic QS, peroxiredoxin from <i>Aeropyrum pernix</i> K1 (ApPrx) forms a decamer, wherein five dimers associate to form a ring. Here, we disrupted and reconstituted ApPrx QS via amino acid mutations and chemical modifications targeting hot spots for protein assembly. The decameric QS of an ApPrx* mutant, wherein all cysteine residues in wild-type ApPrx were mutated to serine, was destructed to dimers via an F80C mutation. The dimeric ApPrx*F80C mutant was then modified with a small molecule and successfully assembled as a decamer. Structural analysis confirmed that an artificially installed chemical moiety potentially facilitates suitable protein-protein interactions to rebuild a native structure. Rebuilding of dodecamer was also achieved through an additional amino acid mutation. This study describes a facile method to regulate protein assembly state.

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.

scholarly journals FrustratometeR: an R-package to compute Local frustration in protein structures, point mutants and MD simulations

2020 ◽  
Author(s):  
Atilio O. Rausch ◽  
Maria I. Freiberger ◽  
Cesar O. Leonetti ◽  
Diego M. Luna ◽  
Leandro G. Radusky ◽  
...  
Keyword(s):  
Protein Interactions ◽  
Large Scale ◽  
Protein Structures ◽  
Md Simulations ◽  
R Package ◽  
Protein Protein Interactions ◽  
Large Scale Analysis ◽  
Functional Aspects ◽  
Catalytic Sites ◽  
Polypeptide Chains

Once folded natural protein molecules have few energetic conflicts within their polypeptide chains. Many protein structures do however contain regions where energetic conflicts remain after folding, i.e. they have highly frustrated regions. These regions, kept in place over evolutionary and physiological timescales, are related to several functional aspects of natural proteins such as protein-protein interactions, small ligand recognition, catalytic sites and allostery. Here we present FrustratometeR, an R package that easily computes local energetic frustration on a personal computer or a cluster. This package facilitates large scale analysis of local frustration, point mutants and MD trajectories, allowing straightforward integration of local frustration analysis in to pipelines for protein structural analysis.Availability and implementation: https://github.com/proteinphysiologylab/frustratometeR

Small Molecules Targeting Protein–Protein Interactions: A Promising Anti-HIV Strategy

2010 ◽  
Vol 86 (1) ◽  
pp. A32
Author(s):  
Alba Chimirri ◽  
Laura De Luca ◽  
Stefania Ferro ◽  
Rosaria Gitto ◽  
Anna Maria Monforte ◽  
...  
Keyword(s):  
Small Molecules ◽  
Protein Interactions ◽  
Protein Protein Interactions ◽  
Anti Hiv

Engineering an acetyllysine reader with photocrosslinking amino acid for interactome profiling

2021 ◽  
Author(s):  
Babu Sudhamalla ◽  
Anirban Roy ◽  
Soumen Barman ◽  
Jyotirmayee Padhan
Keyword(s):  
Amino Acids ◽  
Amino Acid ◽  
Protein Interactions ◽  
Unnatural Amino Acids ◽  
Protein Protein Interactions ◽  
Site Specific ◽  
Powerful Approach

The site-specific installation of light-activable crosslinker unnatural amino acids offers a powerful approach to trap transient protein-protein interactions both in vitro and in vivo. Herein, we engineer a bromodomain to...

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