scholarly journals Can Precision Electrophile Signaling Make a Meaningful and Lasting Impression in Drug Design?

2021 ◽  
Author(s):  
Marcus Long ◽  
Amogh Kulkarni ◽  
Yimon Aye
Keyword(s):  
Drug Design ◽  
Signaling Pathways ◽  
Residence Time ◽  
Binding Sites ◽  
Inhibitor Design ◽  
Protein Targets ◽  
Protein Target ◽  
Target Spectrum ◽  
Lasting Impression ◽  
Inhibitor Kinetics

For several years, drugs bearing reactive electrophilic appendages have been developed. These units typically confer prolonged residence time of the drugs on their protein targets, and may assist targeting shallow binding sites and/or improving drug-protein target spectrum. Studies on natural electrophilic molecules have indicated that in many instances natural electrophiles use similar mechanisms to alter signaling pathways. However, natural reactive species are also endowed with other important mechanisms to hone signaling properties that are uncommon in drug design. These include ability to be active at low occupancy and elevated inhibitor kinetics. Here we discuss how we have begun to harness these properties in inhibitor design.

scholarly journals Feasibility of achieving different protein targets using a hypocaloric high-protein enteral formula in critically ill patients

Critical Care ◽  
2021 ◽  
Vol 25 (1) ◽  
Author(s):  
Pierre Singer ◽  
Itai Bendavid ◽  
Ilana BenArie ◽  
Liran Stadlander ◽  
Ilya Kagan
Keyword(s):  
Critically Ill ◽  
Nitrogen Balance ◽  
High Protein ◽  
Nitrogen Excretion ◽  
Protein Targets ◽  
Protein Target ◽  
Group A ◽  
Group B ◽  
Urinary Nitrogen Excretion ◽  
Urinary Nitrogen

Abstract Background and aims Combining energy and protein targets during the acute phase of critical illness is challenging. Energy should be provided progressively to reach targets while avoiding overfeeding and ensuring sufficient protein provision. This prospective observational study evaluated the feasibility of achieving protein targets guided by 24-h urinary nitrogen excretion while avoiding overfeeding when administering a high protein-to-energy ratio enteral nutrition (EN) formula. Methods Critically ill adult mechanically ventilated patients with an APACHE II score > 15, SOFA > 4 and without gastrointestinal dysfunction received EN with hypocaloric content for 7 days. Protein need was determined by 24-h urinary nitrogen excretion, up to 1.2 g/kg (Group A, N = 10) or up to 1.5 g/kg (Group B, N = 22). Variables assessed included nitrogen intake, excretion, balance; resting energy expenditure (REE); phase angle (PhA); gastrointestinal tolerance of EN. Results Demographic characteristics of groups were similar. Protein target was achieved using urinary nitrogen excretion measurements. Nitrogen balance worsened in Group A but improved in Group B. Daily protein and calorie intake and balance were significantly increased in Group B compared to Group A. REE was correlated to PhA measurements. Gastric tolerance of EN was good. Conclusions Achieving the protein target using urinary nitrogen loss up to 1.5 g/kg/day was feasible in this hypercatabolic population. Reaching a higher protein and calorie target did not induce higher nitrogen excretion and was associated with improved nitrogen balance and a better energy intake without overfeeding. PhA appears to be related to REE and may reflect metabolism level, suggestive of a new phenotype for nutritional status. Trial registration 0795-18-RMC.

scholarly journals Detection of secondary binding sites in proteins using fragment screening

2015 ◽  
Vol 112 (52) ◽  
pp. 15910-15915 ◽  
Author(s):  
R. Frederick Ludlow ◽  
Marcel L. Verdonk ◽  
Harpreet K. Saini ◽  
Ian J. Tickle ◽  
Harren Jhoti
Keyword(s):  
Binding Site ◽  
Binding Sites ◽  
Cellular Functions ◽  
Modulate Function ◽  
Protein Targets ◽  
Biologically Relevant ◽  
X Ray Crystallography ◽  
Fragment Screening ◽  
High Conservation ◽  
Partner Proteins

Proteins need to be tightly regulated as they control biological processes in most normal cellular functions. The precise mechanisms of regulation are rarely completely understood but can involve binding of endogenous ligands and/or partner proteins at specific locations on a protein that can modulate function. Often, these additional secondary binding sites appear separate to the primary binding site, which, for example for an enzyme, may bind a substrate. In previous work, we have uncovered several examples in which secondary binding sites were discovered on proteins using fragment screening approaches. In each case, we were able to establish that the newly identified secondary binding site was biologically relevant as it was able to modulate function by the binding of a small molecule. In this study, we investigate how often secondary binding sites are located on proteins by analyzing 24 protein targets for which we have performed a fragment screen using X-ray crystallography. Our analysis shows that, surprisingly, the majority of proteins contain secondary binding sites based on their ability to bind fragments. Furthermore, sequence analysis of these previously unknown sites indicate high conservation, which suggests that they may have a biological function, perhaps via an allosteric mechanism. Comparing the physicochemical properties of the secondary sites with known primary ligand binding sites also shows broad similarities indicating that many of the secondary sites may be druggable in nature with small molecules that could provide new opportunities to modulate potential therapeutic targets.

scholarly journals Arabinosyl transferase inhibitor design against Mycobacterium tuberculosis using ligand based drug design approach

2014 ◽  
Vol 9 (2) ◽  
Author(s):  
Bhaskor Kolita ◽  
Dhrubajyoti Gogoi ◽  
Partha Pratim Dutta ◽  
Manobjyoti Bordoloi ◽  
Rajib Lochan Bezbaruah
Keyword(s):  
Mycobacterium Tuberculosis ◽  
Drug Design ◽  
Design Approach ◽  
Inhibitor Design

scholarly journals Unique N-Terminal Interactions Connect F-BOX STRESS INDUCED (FBS) Proteins to a WD40 Repeat-like Protein Pathway in Arabidopsis

Plants ◽  
2021 ◽  
Vol 10 (10) ◽  
pp. 2228
Author(s):  
Edgar Sepulveda-Garcia ◽  
Elena C. Fulton ◽  
Emily V. Parlan ◽  
Lily E. O’Connor ◽  
Anneke A. Fleming ◽  
...  
Keyword(s):  
Environmental Stress ◽  
Biological Function ◽  
Interacting Proteins ◽  
Wd40 Repeat ◽  
Protein Targets ◽  
Scf Complex ◽  
Protein Target ◽  
The Core ◽  
N Terminus ◽  
Nuclear Events

SCF-type E3 ubiquitin ligases provide specificity to numerous selective protein degradation events in plants, including those that enable survival under environmental stress. SCF complexes use F-box (FBX) proteins as interchangeable substrate adaptors to recruit protein targets for ubiquitylation. FBX proteins almost universally have structure with two domains: A conserved N-terminal F-box domain interacts with a SKP protein and connects the FBX protein to the core SCF complex, while a C-terminal domain interacts with the protein target and facilitates recruitment. The F-BOX STRESS INDUCED (FBS) subfamily of plant FBX proteins has an atypical structure, however, with a centrally located F-box domain and additional conserved regions at both the N- and C-termini. FBS proteins have been linked to environmental stress networks, but no ubiquitylation target(s) or biological function has been established for this subfamily. We have identified two WD40 repeat-like proteins in Arabidopsis that are highly conserved in plants and interact with FBS proteins, which we have named FBS INTERACTING PROTEINs (FBIPs). FBIPs interact exclusively with the N-terminus of FBS proteins, and this interaction occurs in the nucleus. FBS1 destabilizes FBIP1, consistent with FBIPs being ubiquitylation targets SCFFBS1 complexes. This work indicates that FBS proteins may function in stress-responsive nuclear events, and it identifies two WD40 repeat-like proteins as new tools with which to probe how an atypical SCF complex, SCFFBS, functions via FBX protein N-terminal interaction events.

scholarly journals The Promise of Integrins as Effective Targets for Anticancer Agents

2002 ◽  
Vol 2 (3) ◽  
pp. 124-130 ◽  
Author(s):  
William L. Rust ◽  
Stephen W. Carper ◽  
George E. Plopper
Keyword(s):  
Monoclonal Antibodies ◽  
Drug Design ◽  
Cell Surface ◽  
Signaling Pathways ◽  
Anticancer Agents ◽  
Chemotherapeutic Agents ◽  
Migration And Invasion ◽  
Chemotherapeutic Drug ◽  
Cellular Processes ◽  
Adenovirus Vectors

This review will briefly describe integrin function, address why integrins are attractive targets for chemotherapeutic drug design, and discuss some ongoing studies aimed at inhibiting integrin activity. Integrins are cell surface heterodimeric receptors. They modulate many cellular processes including: growth, death (apoptosis), adhesion, migration, and invasion by activating several signaling pathways. Many potential chemotherapeutic agents target integrins directly (eg, polypeptides, monoclonal antibodies, adenovirus vectors). These agents may be clinically useful in controlling the metastatic spread of cancer.

3D U-Net: A voxel-based method in binding site prediction of protein structure

2021 ◽  
Vol 19 (02) ◽  
pp. 2150006
Author(s):  
Fatemeh Nazem ◽  
Fahimeh Ghasemi ◽  
Afshin Fassihi ◽  
Alireza Mehri Dehnavi
Keyword(s):  
Drug Design ◽  
Binding Site ◽  
Binding Sites ◽  
Semantic Segmentation ◽  
Structure Based Drug Design ◽  
Site Prediction ◽  
Binding Site Prediction ◽  
Novel Proteins ◽  
Proposed Model ◽  
Deep Learning Model

Binding site prediction for new proteins is important in structure-based drug design. The identified binding sites may be helpful in the development of treatments for new viral outbreaks in the world when there is no information available about their pockets with COVID-19 being a case in point. Identification of the pockets using computational methods, as an alternative method, has recently attracted much interest. In this study, the binding site prediction is viewed as a semantic segmentation problem. An improved 3D version of the U-Net model based on the dice loss function is utilized to predict the binding sites accurately. The performance of the proposed model on the independent test datasets and SARS-COV-2 shows the segmentation model could predict the binding sites with a more accurate shape than the recently published deep learning model, i.e. DeepSite. Therefore, the model may help predict the binding sites of proteins and could be used in drug design for novel proteins.

scholarly journals Elucidating the druggable interface of protein−protein interactions using fragment docking and coevolutionary analysis

2016 ◽  
Vol 113 (50) ◽  
pp. E8051-E8058 ◽  
Author(s):  
Fang Bai ◽  
Faruck Morcos ◽  
Ryan R. Cheng ◽  
Hualiang Jiang ◽  
José N. Onuchic
Keyword(s):  
Drug Design ◽  
Protein Interactions ◽  
Binding Sites ◽  
Hot Spots ◽  
Therapeutic Agents ◽  
Molecular Probes ◽  
Therapeutic Drug ◽  
Protein Protein Interactions ◽  
Protein Surface ◽  
Fragment Docking

Protein−protein interactions play a central role in cellular function. Improving the understanding of complex formation has many practical applications, including the rational design of new therapeutic agents and the mechanisms governing signal transduction networks. The generally large, flat, and relatively featureless binding sites of protein complexes pose many challenges for drug design. Fragment docking and direct coupling analysis are used in an integrated computational method to estimate druggable protein−protein interfaces. (i) This method explores the binding of fragment-sized molecular probes on the protein surface using a molecular docking-based screen. (ii) The energetically favorable binding sites of the probes, called hot spots, are spatially clustered to map out candidate binding sites on the protein surface. (iii) A coevolution-based interface interaction score is used to discriminate between different candidate binding sites, yielding potential interfacial targets for therapeutic drug design. This approach is validated for important, well-studied disease-related proteins with known pharmaceutical targets, and also identifies targets that have yet to be studied. Moreover, therapeutic agents are proposed by chemically connecting the fragments that are strongly bound to the hot spots.

Upregulated Signaling Pathways in Ruptured Human Saccular Intracranial Aneurysm Wall: An Emerging Regulative Role of Toll-Like Receptor Signaling and Nuclear Factor-κB, Hypoxia-Inducible Factor-1A, and ETS Transcription Factors

Neurosurgery ◽  
2011 ◽  
Vol 68 (6) ◽  
pp. 1667-1676 ◽  
Author(s):  
Mitja I. Kurki ◽  
Sanna-Kaisa Häkkinen ◽  
Juhana Frösen ◽  
Riikka Tulamo ◽  
Mikael von und zu Fraunberg ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Intracranial Aneurysm ◽  
Signaling Pathways ◽  
Binding Sites ◽  
Hypoxia Inducible Factor ◽  
Transcription Factor Binding Sites ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Toll Like Receptor ◽  
Factor Binding

Abstract BACKGROUND: Aneurysmal subarachnoid hemorrhage, almost always from saccular intracranial aneurysm (sIA), is a devastating form of stroke that affects the working-age population. Cellular and molecular mechanisms predisposing to the rupture of the sIA wall are largely unknown. This knowledge would facilitate the design of novel diagnostic tools and therapies for the sIA disease. OBJECTIVE: To investigate gene expression patterns distinguishing ruptured and unruptured sIA. METHODS: We compared the whole-genome expression profile of 11 ruptured sIA wall samples with that of 8 unruptured ones using oligonucleotide microarrays. Signaling pathways enriched in the ruptured sIA walls were identified with bioinformatic analyses. Their transcriptional control was predicted in silico by seeking the enrichment of conserved transcription factor binding sites in the promoter regions of differentially expressed genes. RESULTS: Overall, 686 genes were significantly upregulated and 740 were downregulated in the ruptured sIA walls. Significantly upregulated biological processes included response to turbulent blood flow, chemotaxis, leukocyte migration, oxidative stress, vascular remodeling; and extracellular matrix degradation. Toll-like receptor signaling and nuclear factor-κB, hypoxia-inducible factor-1A, and ETS transcription factor binding sites were significantly enriched among the upregulated genes. CONCLUSION: We identified pathways and candidate genes associated with the rupture of human sIA wall. Our results may provide clues to the molecular mechanism in sIA wall rupture and insight for novel therapeutic strategies to prevent rupture.

scholarly journals c-Kit-Mediated Overlapping and Unique Functional and Biochemical Outcomes via Diverse Signaling Pathways

2004 ◽  
Vol 24 (3) ◽  
pp. 1401-1410 ◽  
Author(s):  
Li Hong ◽  
Veerendra Munugalavadla ◽  
Reuben Kapur
Keyword(s):  
Signaling Pathways ◽  
Binding Sites ◽  
Cellular Proliferation ◽  
Critical Issue ◽  
Cellular Growth ◽  
Mitogen Activated Protein Kinase ◽  
Downstream Signaling ◽  
Kit Receptor ◽  
And Migration ◽  
The Individual

ABSTRACT A critical issue in understanding receptor tyrosine kinase signaling is the individual contribution of diverse signaling pathways in regulating cellular growth, survival, and migration. We generated a functionally and biochemically inert c-Kit receptor that lacked the binding sites for seven early signaling pathways. Restoring the Src family kinase (SFK) binding sites in the mutated c-Kit receptor restored cellular survival and migration but only partially rescued proliferation and was associated with the rescue of the Ras/mitogen-activated protein kinase, Rac/JNK kinase, and phosphatidylinositol 3-kinase (PI-3 kinase)/Akt pathways. In contrast, restoring the PI-3 kinase binding site in the mutated receptor did not affect cellular proliferation but resulted in a modest correction in cell survival and migration, despite a complete rescue in the activation of the PI-3 kinase/Akt pathway. Surprisingly, restoring the binding sites for Grb2, Grb7, or phospholipase C-γ had no effect on cellular growth or survival, migration, or activation of any of the downstream signaling pathways. These results argue that SFKs play a unique role in the control of multiple cellular functions and in the activation of distinct biochemical pathways via c-Kit.

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