scholarly journals A New Native Mass Spectrometry Platform Identifies Inhibitors of the HSP90 – HOP Protein-Protein Interaction

2020 ◽  
Author(s):  
Clinton Veale ◽  
Mateos-Jimenez, Maria ◽  
Michaelone Vaaltyn ◽  
Ronel Müller ◽  
Matodzi Makhubu ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Drug Discovery ◽  
Protein Interaction ◽  
Drug Target ◽  
Native Mass Spectrometry ◽  
Cancer Drug ◽  
Protein Protein Interaction ◽  
Cancer Drug Discovery ◽  
First Time

This communication discusses for the first time, the use of mass spectrometry as a platform for screening for PPI inhibitors, without protein tethering or labeling. Furthermore, in the context of cancer drug discovery, this study demonstrates the ligandability and therefore the potential druggability of HOP, whose PPI with HSP90 has been routinely discussed as a difficult to drug target of substantial potential.

scholarly journals A New Native Mass Spectrometry Platform Identifies Inhibitors of the HSP90 – HOP Protein-Protein Interaction

2020 ◽  
Author(s):  
Clinton Veale ◽  
Mateos-Jimenez, Maria ◽  
Michaelone Vaaltyn ◽  
Ronel Müller ◽  
Matodzi Makhubu ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Drug Discovery ◽  
Protein Interaction ◽  
Drug Target ◽  
Native Mass Spectrometry ◽  
Cancer Drug ◽  
Protein Protein Interaction ◽  
Cancer Drug Discovery ◽  
First Time

This communication discusses for the first time, the use of mass spectrometry as a platform for screening for PPI inhibitors, without protein tethering or labeling. Furthermore, in the context of cancer drug discovery, this study demonstrates the ligandability and therefore the potential druggability of HOP, whose PPI with HSP90 has been routinely discussed as a difficult to drug target of substantial potential.

scholarly journals An Application of Fit Quality to Screen MDM2/p53 Protein-Protein Interaction Inhibitors

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3174 ◽  
Author(s):  
Xin Xue ◽  
Gang Bao ◽  
Hai-Qing Zhang ◽  
Ning-Yi Zhao ◽  
Yuan Sun ◽  
...  
Keyword(s):  
Protein Interaction ◽  
Drug Target ◽  
P53 Protein ◽  
Pharmacophore Model ◽  
Cellular Level ◽  
Complex Structures ◽  
Ligand Complex ◽  
Null Cell ◽  
Protein Protein Interaction ◽  
First Time

: The judicious application of ligand or binding efficiency (LE) metrics, which quantify the molecular properties required to obtain binding affinity for a drug target, is gaining traction in the selection and optimization of fragments, hits and leads. Here we report for the first time the use of LE based metric, fit quality (FQ), in virtual screening (VS) of MDM2/p53 protein-protein interaction inhibitors (PPIIs). Firstly, a Receptor-Ligand pharmacophore model was constructed on multiple MDM2/ligand complex structures to screen the library. The enrichment factor (EF) for screening was calculated based on a decoy set to define the screening threshold. Finally, 1% of the library, 335 compounds, were screened and re-filtered with the FQ metric. According to the statistical results of FQ vs activity of 156 MDM2/p53 PPIIs extracted from literatures, the cut-off was defined as FQ = 0.8. After the second round of VS, six compounds with the FQ > 0.8 were picked out for assessing their antitumor activity. At the cellular level, the six hits exhibited a good selectivity (larger than 3) against HepG2 (wt-p53) vs Hep3B (p53 null) cell lines. On the further study, the six hits exhibited an acceptable affinity (range of Ki from 102 to 103 nM) to MDM2 when comparing to Nutlin-3a. Based on our work, FQ based VS strategy could be applied to discover other PPIIs.

scholarly journals Discovery of a Natural Product That Binds to the Mycobacterium tuberculosis Protein Rv1466 Using Native Mass Spectrometry

Molecules ◽  
2020 ◽  
Vol 25 (10) ◽  
pp. 2384
Author(s):  
Ali R. Elnaas ◽  
Darren Grice ◽  
Jianying Han ◽  
Yunjiang Feng ◽  
Angela Di Capua ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Mycobacterium Tuberculosis ◽  
Drug Discovery ◽  
Drug Target ◽  
Inhibitory Concentration ◽  
Native Mass Spectrometry ◽  
Cellular Activity ◽  
Future Drug ◽  
Mycobacterial Protein

Elucidation of the mechanism of action of compounds with cellular bioactivity is important for progressing compounds into future drug development. In recent years, phenotype-based drug discovery has become the dominant approach to drug discovery over target-based drug discovery, which relies on the knowledge of a specific drug target of a disease. Still, when targeting an infectious disease via a high throughput phenotypic assay it is highly advantageous to identifying the compound’s cellular activity. A fraction derived from the plant Polyalthia sp. showed activity against Mycobacterium tuberculosis at 62.5 μge/μL. A known compound, altholactone, was identified from this fraction that showed activity towards M. tuberculosis at an minimum inhibitory concentration (MIC) of 64 μM. Retrospective analysis of a target-based screen against a TB proteome panel using native mass spectrometry established that the active fraction was bound to the mycobacterial protein Rv1466 with an estimated pseudo-Kd of 42.0 ± 6.1 µM. Our findings established Rv1466 as the potential molecular target of altholactone, which is responsible for the observed in vivo toxicity towards M. tuberculosis.

A native mass spectrometry platform identifies HOP inhibitors that modulate the HSP90–HOP protein–protein interaction

2021 ◽  
Author(s):  
Clinton G. L. Veale ◽  
Maria Mateos-Jiménez ◽  
Michaelone C. Vaaltyn ◽  
Ronel Müller ◽  
Matodzi P. Makhubu ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Protein Interaction ◽  
Protein Interactions ◽  
Native Mass Spectrometry ◽  
Protein Protein Interactions ◽  
Protein Protein Interaction

We demonstrate the potential of native mass spectrometry for modelling Protein–Protein Interactions, leading to the identification of inhibitors of the HSP90–HOP PPI.

scholarly journals Discovering protein–protein interaction stabilisers by native mass spectrometry

2021 ◽  
Author(s):  
Jeddidiah Bellamy-Carter ◽  
Manjari Mohata ◽  
Marta Falcicchio ◽  
Jaswir Basran ◽  
Yusuke Higuchi ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Protein Interaction ◽  
Protein Interactions ◽  
Native Mass Spectrometry ◽  
Protein Protein Interactions ◽  
Protein Protein Interaction ◽  
Novel Protein

Stabilising protein–protein interactions is challenging, yet therapeutically important. Native mass spectrometry can be used to monitor binding equilibria, allowing identification and measurement of novel protein–protein interaction stabilisers.

Protein-Protein Interaction (PPI) Network: Recent Advances in Drug Discovery

2017 ◽  
Vol 18 (1) ◽  
pp. 5-10 ◽  
Author(s):  
Alexiou Athanasios ◽  
Vairaktarakis Charalampos ◽  
Tsiamis Vasileios ◽  
Ghulam Ashraf
Keyword(s):  
Drug Discovery ◽  
Protein Interaction ◽  
Ppi Network ◽  
Protein Protein Interaction ◽  
Recent Advances

Scaffold Repurposing of Old Drugs Towards New Cancer Drug Discovery

2016 ◽  
Vol 16 (19) ◽  
pp. 2107-2114 ◽  
Author(s):  
Haijun Chen ◽  
Jianlei Wu ◽  
Yu Gao ◽  
Haiying Chen ◽  
Jia Zhou
Keyword(s):  
Drug Discovery ◽  
Cancer Drug ◽  
Cancer Drug Discovery ◽  
Old Drugs

Natural Sesquiterpene Lactones in the Prevention and Treatment of Inflammatory Disorders and cancer: A Systematic Study of this Emerging Therapeutic Approach based on Chemical and Pharmacological Aspect

2020 ◽  
Vol 17 (9) ◽  
pp. 1102-1116
Author(s):  
Sudip Kumar Mandal ◽  
Utsab Debnath ◽  
Amresh Kumar ◽  
Sabu Thomas ◽  
Subhash Chandra Mandal ◽  
...  
Keyword(s):  
Drug Discovery ◽  
Biological Activities ◽  
Sesquiterpene Lactones ◽  
Structural Diversity ◽  
Cancer Drug ◽  
Cancer Drug Discovery ◽  
Anti Cancer ◽  
Drug Discovery Program ◽  
Anti Inflammatory ◽  
Family Based

Background and Introduction: Sesquiterpene lactones are a class of secondary metabolite that contains sesquiterpenoids and lactone ring as pharmacophore moiety. A large group of bioactive secondary metabolites such as phytopharmaceuticals belong to this category. From the Asteraceae family-based medicinal plants, more than 5,000 sesquiterpene lactones have been reported so far. Sesquiterpene lactone-based pharmacophore moieties hold promise for broad-spectrum biological activities against cancer, inflammation, parasitic, bacterial, fungal, viral infection and other functional disorders. Moreover, these moiety based phytocompounds have been highlighted with a new dimension in the natural drug discovery program worldwide after the 2015 Medicine Nobel Prize achieved by the Artemisinin researchers. Objective: These bitter substances often contain an α, β-unsaturated-γ-lactone as a major structural backbone, which in recent studies has been explored to be associated with anti-tumor, cytotoxic, and anti-inflammatory action. Recently, the use of sesquiterpene lactones as phytomedicine has been increased. This study will review the prospect of sesquiterpene lactones against inflammation and cancer. Methods: Hence, we emphasized on the different features of this moiety by incorporating its structural diversity on biological activities to explore structure-activity relationships (SAR) against inflammation and cancer. Results: How the dual mode of action such as anti-inflammatory and anti-cancer has been exhibitedby these phytopharmaceuticals will be forecasted in this study. Furthermore, the correlation of anti-inflammatory and anti-cancer activity executed by the sesquiterpene lactones for fruitful phytotherapy will also be revealed in the present review in the milieu of pharmacophore activity relation and pharmacodynamics study as well. Conclusion: So, these metabolites are paramount in phytopharmacological aspects. The present discussion on the future prospect of this moiety based on the reported literature could be a guide for anti-inflammatory and anti-cancer drug discovery programs for the upcoming researchers.

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