Intrinsically Disordered Proteins as Drug Targets

Martinez, Melchor Sanchez

doi:10.15406/mojpb.2017.05.00157

Cited by 3 publications

(4 citation statements)

References 56 publications

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“…K i = 1.02 μM, 0.60 μM, 0.39 μM and 0.32 μM, respectively (entries 1,5,11,16). The same correlation applies to the osubstituted halogens (o-F < o-Cl < o-Br < o-I), giving even higher binding affinities (K i = 0.74 μM, 0.36 μM, 0.07 μM and 0.05 μM, respectively (entries 3,7,13,18)). Clearly, these trends show a size-dependent activity, driven by the σ-hole, relationship being in accordance with literature [47,49].…”

Section: Probe Of Leu26 and Induced Pocketmentioning

confidence: 73%

“…Drug discovery remains slow, expensive and unreliable. Although immense progress in individual whole genome sequencing for personalized medicine has provided a wealth of novel drug targets, very few small molecule drugs for post-genomic identified targets are currently in development [1][2][3]. A major hurdle to the efficient and fast generation of novel drugs is the slow and traditional approach performed in early drug discovery and development.…”

Section: Introductionmentioning

confidence: 99%

“…The determined conformations of a protein often differ in its ligand-bound and unbound forms. Protein conformational changes could open new ligand binding sites, whose exploration is a key to fully access the efficacy of a drug as well as to identify non-specific targeting with possible undesired effects [3][4][5][6][7]. Intrinsically disordered protein states (IDPs) are an emerging family of proteins whose most characteristic feature is that they don't present a folded structure, and thus challenge the sequence-structure-function paradigm [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

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Hitting on the move: Targeting intrinsically disordered protein states of the MDM2-p53 interaction

Neochoritis

Atmaj

Twarda-Cłapa

et al. 2019

European Journal of Medicinal Chemistry

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Intrinsically disordered proteins are an emerging class of proteins without a folded structure and currently disorder-based drug targeting remains a challenge. p53 is the principal regulator of cell division and growth whereas MDM2 consists its main negative regulator. The MDM2-p53 recognition is a dynamic and multistage process that amongst other, employs the dissociation of a transient α-helical N-terminal "lid" segment of MDM2 from the proximity of the p53complementary interface. Several small molecule inhibitors have been reported to inhibit the formation of the p53-MDM2 complex with the vast majority mimicking the p53 residues Phe19, Trp23 and Leu26. Recently, we have described the transit from the 3-point to 4-point pharmacophore model stabilizing this intrinsically disordered N-terminus by increasing the binding affinity by a factor of 3. Therefore, we performed a thorough SAR analysis, including chiral separation of key compound which was evaluated by FP and 2D NMR. Finally, p53-specific anti-cancer activity towards p53-wild-type cancer cells was observed for several representative compounds.

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Section: Probe Of Leu26 and Induced Pocketmentioning

confidence: 73%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Hitting on the move: Targeting intrinsically disordered protein states of the MDM2-p53 interaction

Neochoritis

Atmaj

Twarda-Cłapa

et al. 2019

European Journal of Medicinal Chemistry

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“…These membraneless condensates would either act as a signaling platform to activate oncogenic pathways or assemble as transcriptional complexes to promote oncogenic gene expression, both of which could result in carcinogenesis (52)(53)(54)(55). Therefore, the discovery of drugs to disrupt multivalent protein-protein interactions would be an excellent choice to disassemble aberrant biocondensates and block tumor signal transduction for anticancer effects (56,57). Cluster 3 was related to the role of DNA and RNA elements in phase separation-related diseases; it covered the keywords of chromatin, enhancer elements, neurodegenerative diseases, RNA-binding protein, RNA, disease, and gene expression regulation.…”

Section: Abstract and Future Hotspotsmentioning

confidence: 99%

The global landscape and research trend of phase separation in cancer: a bibliometric analysis and visualization

Zhang

Zhao

et al. 2023

Front. Oncol.

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BackgroundCancer as a deathly disease with high prevalence has impelled researchers to investigate its causative mechanisms in the search for effective therapeutics. Recently, the concept of phase separation has been introduced to biological science and extended to cancer research, which helps reveal various pathogenic processes that have not been identified before. As a process of soluble biomolecules condensed into solid-like and membraneless structures, phase separation is associated with multiple oncogenic processes. However, there are no bibliometric characteristics for these results. To provide future trends and identify new frontiers in this field, a bibliometric analysis was conducted in this study.MethodsThe Web of Science Core Collection (WoSCC) was used to search for literature on phase separation in cancer from 1/1/2009 to 31/12/2022. After screening the literature, statistical analysis and visualization were carried out by the VOSviewer software (version 1.6.18) and Citespace software (Version 6.1.R6).ResultsA total of 264 publications, covering 413 organizations and 32 countries, were published in 137 journals, with an increasing trend in publication and citation numbers per year. The USA and China were the two countries with the largest number of publications, and the University of Chinese Academy of Sciences was the most active institution based on the number of articles and cooperations. Molecular Cell was the most frequent publisher with high citations and H-index. The most productive authors were Fox AH, De Oliveira GAP, and Tompa P. Overlay, whilst few authors had a strong collaboration with each other. The combined analysis of concurrent and burst keywords revealed that the future research hotspots of phase separation in cancer were related to tumor microenvironments, immunotherapy, prognosis, p53, and cell death.ConclusionPhase separation-related cancer research remained in the hot streak period and exhibited a promising outlook. Although inter-agency collaboration existed, cooperation among research groups was rare, and no author dominated this field at the current stage. Investigating the interfaced effects between phase separation and tumor microenvironments on carcinoma behaviors, and constructing relevant prognoses and therapeutics such as immune infiltration-based prognosis and immunotherapy might be the next research trend in the study of phase separation and cancer.

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The State of Proteins not with Standing, Translational Velocity is Vital for their Function

Udema¹,

Onigbinde

2019

AJRB

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Background: Targeting of macromolecules by means of translational diffusion for therapeutic reason is generally of interest. But translational velocity that enables directional delivery of any molecule on target is given less attention. Objectives: The objectives of this research are to: 1) determine the value of the cohesion factor affecting solutes, 2) determine the translational velocity of porcine pancreatic (PPAA) - and human salivary (HSAA) – alpha amylase and ions, 3) rederive the effective kinetic energy (K.E.) of solutes, 4) determine the thermodynamic parameters for a folded to an unfolded transition and 5) give reasons why the velocity of solution components is generally very important. Methods: A theoretical research and experimentation using Bernfeld method. Results and Discussion: The K.E. of solution components as re-derived is « 3kBT / 2 (where kB and T are Boltzmann constant and Kelvin temperature respectively.). The velocities of hydrolysis of the substrate with the sucrose-treated PPAA were generally higher than those of HSAA. The values of conformational entropy change (∆Sconf) for PPAA were generally higher than those of HSAA. Expectedly the values of ∆Sconf were positive. Conclusion: In conclusion, the square root of the cohesion factor is larger than 22.4 exp (+3) 310.15 K / 273.15 K / 18, accounting for the translational velocity (u) in solution being « gas phase velocity (U). The translational diffusion D and u remain respectively, a function of the hydrodynamic radius of the solutes in particular and the magnitude of D; unfolding of proteins decreases the values of the parameters. Overall, unfolding is entropy driven. Without the mobility of solution components at desired velocity directional delivery of small molecules to site of need such as intrinsically disordered proteins etc may remain impossible.

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Intrinsically Disordered Proteins as Drug Targets

Cited by 3 publications

References 56 publications

Hitting on the move: Targeting intrinsically disordered protein states of the MDM2-p53 interaction

Hitting on the move: Targeting intrinsically disordered protein states of the MDM2-p53 interaction

The global landscape and research trend of phase separation in cancer: a bibliometric analysis and visualization

The State of Proteins not with Standing, Translational Velocity is Vital for their Function

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