Targeting of Disordered Proteins by Small Molecules in Neurodegenerative Diseases

2017 ◽  
pp. 85-110 ◽  
Author(s):  
Francesca Longhena ◽  
PierFranco Spano ◽  
Arianna Bellucci
Keyword(s):  
Neurodegenerative Diseases ◽  
Small Molecules ◽  
Disordered Proteins

Current Challenges and Limitations in the Studies of Intrinsically Disordered Proteins in Neurodegenerative Diseases by Computer Simulations

2020 ◽  
Vol 17 ◽  
Author(s):  
Ibrahim Yagiz Akbayrak ◽  
Sule Irem Caglayan ◽  
Zilan Ozcan ◽  
Vladimir N. Uversky ◽  
Orkid Coskuner-Weber
Keyword(s):  
Neurodegenerative Diseases ◽  
Computer Simulations ◽  
Conformational Changes ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Computational Studies ◽  
Accurate Data ◽  
Aggregation Propensity ◽  
Intrinsically Disordered ◽  
Future Developments

: Experiments face challenges in the analysis of intrinsically disordered proteins in solution due to fast conformational changes and enhanced aggregation propensity. Computational studies complement experiments, being widely used in the analyses of intrinsically disordered proteins, especially those positioned at the centers of neurodegenerative diseases. However, recent investigations – including our own – revealed that computer simulations face significant challenges and limitations themselves. In this review, we introduced and discussed some of the scientific challenges and limitations of computational studies conducted on intrinsically disordered proteins. We also outlined the importance of future developments in the areas of computational chemistry and computational physics that would be needed for generating more accurate data for intrinsically disordered proteins from computer simulations. Additional theoretical strategies that can be developed are discussed herein.

scholarly journals Targeting Intrinsically Disordered Proteins through Dynamic Interactions

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 743
Author(s):  
Jianlin Chen ◽  
Xiaorong Liu ◽  
Jianhan Chen
Keyword(s):  
Small Molecules ◽  
Intrinsically Disordered Proteins ◽  
Gpu Computing ◽  
Disordered Proteins ◽  
Atomistic Simulations ◽  
Conformational Ensemble ◽  
Processing Unit ◽  
Dynamic Interactions ◽  
Intrinsically Disordered ◽  
Interaction Sites

Intrinsically disordered proteins (IDPs) are over-represented in major disease pathways and have attracted significant interest in understanding if and how they may be targeted using small molecules for therapeutic purposes. While most existing studies have focused on extending the traditional structure-centric drug design strategies and emphasized exploring pre-existing structure features of IDPs for specific binding, several examples have also emerged to suggest that small molecules could achieve specificity in binding IDPs and affect their function through dynamic and transient interactions. These dynamic interactions can modulate the disordered conformational ensemble and often lead to modest compaction to shield functionally important interaction sites. Much work remains to be done on further elucidation of the molecular basis of the dynamic small molecule–IDP interaction and determining how it can be exploited for targeting IDPs in practice. These efforts will rely critically on an integrated experimental and computational framework for disordered protein ensemble characterization. In particular, exciting advances have been made in recent years in enhanced sampling techniques, Graphic Processing Unit (GPU)-computing, and protein force field optimization, which have now allowed rigorous physics-based atomistic simulations to generate reliable structure ensembles for nontrivial IDPs of modest sizes. Such de novo atomistic simulations will play crucial roles in exploring the exciting opportunity of targeting IDPs through dynamic interactions.

scholarly journals Targeting New Candidate Genes by Small Molecules Approaching Neurodegenerative Diseases

2015 ◽  
Vol 17 (1) ◽  
pp. 26 ◽  
Author(s):  
Hueng-Chuen Fan ◽  
Ching-Shiang Chi ◽  
Shin-Nan Cheng ◽  
Hsiu-Fen Lee ◽  
Jeng-Dau Tsai ◽  
...  
Keyword(s):  
Neurodegenerative Diseases ◽  
Small Molecules ◽  
Candidate Genes

Regulation of autophagy by mTOR-dependent and mTOR-independent pathways: autophagy dysfunction in neurodegenerative diseases and therapeutic application of autophagy enhancers

2013 ◽  
Vol 41 (5) ◽  
pp. 1103-1130 ◽  
Author(s):  
Sovan Sarkar
Keyword(s):  
Neurodegenerative Diseases ◽  
Small Molecules ◽  
Mammalian Target Of Rapamycin ◽  
Degradation Pathway ◽  
Therapeutic Application ◽  
Mutant Proteins ◽  
Chemical Inducers ◽  
Intracellular Degradation ◽  
Wide Range ◽  
Potential Therapeutic Application

Autophagy is an intracellular degradation pathway essential for cellular and energy homoeostasis. It functions in the clearance of misfolded proteins and damaged organelles, as well as recycling of cytosolic components during starvation to compensate for nutrient deprivation. This process is regulated by mTOR (mammalian target of rapamycin)-dependent and mTOR-independent pathways that are amenable to chemical perturbations. Several small molecules modulating autophagy have been identified that have potential therapeutic application in diverse human diseases, including neurodegeneration. Neurodegeneration-associated aggregation-prone proteins are predominantly degraded by autophagy and therefore stimulating this process with chemical inducers is beneficial in a wide range of transgenic disease models. Emerging evidence indicates that compromised autophagy contributes to the aetiology of various neurodegenerative diseases related to protein conformational disorders by causing the accumulation of mutant proteins and cellular toxicity. Combining the knowledge of autophagy dysfunction and the mechanism of drug action may thus be rational for designing targeted therapy. The present review describes the cellular signalling pathways regulating mammalian autophagy and highlights the potential therapeutic application of autophagy inducers in neurodegenerative disorders.

scholarly journals Methods of probing the interactions between small molecules and disordered proteins

2017 ◽  
Vol 74 (17) ◽  
pp. 3225-3243 ◽  
Author(s):  
Gabriella T. Heller ◽  
Francesco A. Aprile ◽  
Michele Vendruscolo
Keyword(s):  
Small Molecules ◽  
Disordered Proteins

scholarly journals Discovery of a potent small molecule inhibiting Huntington’s disease (HD) pathogenesis via targeting CAG repeats RNA and Poly Q protein

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Eshan Khan ◽  
Subodh Kumar Mishra ◽  
Ribhav Mishra ◽  
Amit Mishra ◽  
Amit Kumar
Keyword(s):  
Neurodegenerative Diseases ◽  
Huntington's Disease ◽  
Small Molecules ◽  
Huntington’S Disease ◽  
Cag Repeats ◽  
Spinocerebellar Ataxias ◽  
Cellular Delivery ◽  
Lead Compounds ◽  
The Common ◽  
Search Approach

AbstractCAG repeats RNA causes various fatal neurodegenerative diseases exemplified by Huntington’s disease (HD) and several spinocerebellar ataxias (SCAs). Although there are differences in the pathogenic mechanisms, these diseases share the common cause, i.e., expansion of CAG repeats. The shared cause of these diseases raises the possibility for the exploiting the common target as a potential therapeutic approach. Oligonucleotide-based therapeutics are designed earlier with the help of the base pairing rule but are not very promiscuous, considering the nonspecific stimulation of the immune system and the poor cellular delivery. Therefore, small molecules-based therapeutics are preferred for targeting the repeats expansion disorders. Here, we have used the chemical similarity search approach to discern the small molecules that selectively target toxic CAG RNA. The lead compounds showed the specificity towards AA mismatch in biophysical studies including CD, ITC, and NMR spectroscopy and thus aided to forestall the polyQ mediated pathogenicity. Furthermore, the lead compounds also explicitly alleviate the polyQ mediated toxicity in HD cell models and patient-derived cells. These findings suggest that the lead compound could act as a chemical probe for AA mismatch containing RNA as well as plays a neuroprotective role in fatal neurodegenerative diseases like HD and SCAs.

Characterization of the Binding of Small Molecules to Intrinsically Disordered Proteins

2018 ◽  
pp. 677-702 ◽  
Author(s):  
Veselin S. Dobrev ◽  
Lisette M. Fred ◽  
Kaitlyn P. Gerhart ◽  
Steven J. Metallo
Keyword(s):  
Small Molecules ◽  
Intrinsically Disordered Proteins ◽  
Disordered Proteins ◽  
Intrinsically Disordered
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