Inhibitors of the Oncogenic PA2G4-MYCN Protein-Protein Interface DOI Open Access

Hassina Massudi,

Jie-Si Luo, Jessica K. Holien

и другие.

Cancers, Год журнала: 2023, Номер 15(6), С. 1822 - 1822

Опубликована: Март 17, 2023

MYCN is a major oncogenic driver for neuroblastoma tumorigenesis, yet there are no direct inhibitors. We have previously identified PA2G4 as protein-binding partner of and drive tumorigenesis. A small molecule known to bind PA2G4, WS6, significantly decreased tumorigenicity in TH-MYCN mice, along with the inhibition interactions. Here, we number novel WS6 analogues, 80% structural similarity, used surface plasmon resonance assays determine their binding affinity. Analogues #5333 #5338 showed towards human recombinant PA2G4. Importantly, demonstrated 70-fold lower toxicity normal myofibroblasts compared WS6. Structure-activity relationship analysis that 2,3 dimethylphenol was most suitable substituent at R1 position. Replacing trifluoromethyl group on phenyl ring R2 position, bromine or hydrogen atom, increased difference between efficacy against cells myofibroblast toxicity. The analogues inhibited cell phenotype vitro, part through effects apoptosis, while anti-cancer required both expression. Collectively, chemical PA2G4-MYCN by represents first-in-class drug discovery which may implications other MYCN-driven cancers.

Язык: Английский

Forces Driving a Magic Bullet to Its Target: Revisiting the Role of Thermodynamics in Drug Design, Development, and Optimization DOI Creative Commons
Conceição A.S.A. Minetti, David P. Remeta

Life, Год журнала: 2022, Номер 12(9), С. 1438 - 1438

Опубликована: Сен. 15, 2022

Drug discovery strategies have advanced significantly towards prioritizing target selectivity to achieve the longstanding goal of identifying "magic bullets" amongst thousands chemical molecules screened for therapeutic efficacy. A myriad emerging and existing health threats, including SARS-CoV-2 pandemic, alarming increase in bacterial resistance, potentially fatal chronic ailments, such as cancer, cardiovascular disease, neurodegeneration, incentivized novel therapeutics treatment regimens. The design, development, optimization lead compounds represent an arduous time-consuming process that necessitates assessment specific criteria metrics derived via multidisciplinary approaches incorporating functional, structural, energetic properties. present review focuses on methodologies technologies aimed at advancing drug development with particular emphasis role thermodynamics elucidating underlying forces governing ligand-target interaction specificity. In pursuit therapeutics, isothermal titration calorimetry (ITC) has been utilized extensively over past two decades bolster efforts, yielding information-rich thermodynamic binding signatures. wealth studies recognizes need mining databases critically examine evaluate prospective candidates basis available metrics. ultimate power utility within reside characterization comparison intrinsic signatures facilitate elucidation structural-energetic correlations which assist compound identification improve overall

Язык: Английский

Процитировано

7
Unlocking Neurodegeneration: Scaffold-Derived Blockers of MAO-B and AChE inspired by Bryophyllum pinnatum: A Structural Exploration DOI Creative Commons
Ezekiel A. Olugbogi, Emmanuel Sunday Omirin, Shola D. Omoseeye

и другие.

Research Square (Research Square), Год журнала: 2024, Номер unknown

Опубликована: Янв. 22, 2024

Abstract Alzheimer's disease (AD)and Parkinson's (PD) are progressive neurodegenerative disorders with overlapping symptoms. Reduced acetylcholine levels in AD addressed using Acetylcholinesterase (AChE) inhibitors. Monoamine oxidase B (MAO-B) inhibitors prevent dopamine breakdown PD. Bryophyllum pinnatum , a medicinal plant, that has been used as traditional treatments for various because of its phytochemicals. This study explores ligands potential medications and PD by inhibition AChE MAO-B. Computer-aided drug design was conducted Schrödinger Suite software Maestro 12.8. Ligands from B. standard drugs were docked to the active sites MAO-B AChE. ADMET screening MM/GBSA analysis performed. Pharmacophore modeling identify compounds matching reference ligands. After application all screenings, 4 6 hit found MAO & respectively based on good docking score well properties. Pinoresinol be most potent compounds. These could neuroprotective agent near future. Hence, this provides evidence consideration valuable further vivo vitro investigation might prove their therapeutic potential.

Язык: Английский

Процитировано

1
Solubility-aware protein binding peptide design using AlphaFold DOI Open Access
Takatsugu Kosugi, Masahito Ohue

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2022, Номер unknown

Опубликована: Май 15, 2022

Abstract New protein–protein interactions (PPIs) are being identified, but PPIs have different physicochemical properties compared with conventional targets, making it difficult to use small molecules. Peptides offer a new modality target PPIs, designing appropriate peptide sequences by computation is challenging. Recently, AlphaFold and RosettaFold made possible predict protein structures from amino acid ultra-high accuracy, enabling de novo design. We designed peptides likely PPI as the using “binder hallucination” protocol of AfDesign, design method AlphaFold. However, solubility tended be low. Therefore, we loss function indices for acids developed solubility-aware AfDesign binder hallucination protocol. The in increased weight function; moreover, they captured characteristics indices. Moreover, higher affinity than random or single residue substitution when evaluated docking binding affinity. Our approach shows that can bind interface while controlling solubility.

Язык: Английский

Процитировано

4
Metabolite Profiling of the Environmental-Controlled Growth of Marsilea crenata Presl. and Its In Vitro and In Silico Antineuroinflammatory Properties DOI Creative Commons
Burhan Ma’arif, Faisal Akhmal Muslikh,

Dilla Amalia

и другие.

Borneo Journal of Pharmacy, Год журнала: 2022, Номер 5(3), С. 209 - 228

Опубликована: Авг. 31, 2022

This study was aimed to evaluate the metabolite contents and antineuroinflammatory potential of Marsilea crenata Presl. grown under a controlled environmental condition. The test has been carried out in vitro using ethanolic extract M. leaves on HMC3 microglia cells. An silico approach applied predict active compounds extract. cells were induced with IFNγ create prolonged inflammatory conditions then treated 96% 62.5, 125, 250 μg/mL. expression MHC II analyzed ICC method CLSM instrument. Metabolites profiled UPLC-QToF-MS/MS instrument MassLynx 4.1 software. In evaluation conducted molecular docking 3OLS protein PyRx 0.8 software, physicochemical properties SwissADME webtool. could reduce all concentrations values 97.458, 139.574, 82.128 AU. result profiling found 79 showed that 19 gave agonist interaction toward 3OLS, three met parameters analysis. environmental-controlled growth activity predicted contain some phytoestrogen which act as agonists.

Язык: Английский

Процитировано

4
Comprehensive Analysis of Antidiabetic Properties in Raphanus sativus Leaves: A Synergistic In-Silico and In-Vitro Approach DOI
Sakshar Saha, Pronoy Kanti Das, Prasad Sanjay Dhiwar

и другие.

Chemistry Africa, Год журнала: 2024, Номер 7(9), С. 4757 - 4779

Опубликована: Окт. 25, 2024

Язык: Английский

Процитировано

0
In silico analysis of white turmeric cholorogenic acid compound as angiotensin-converting Enzyme-2 (ACE2) inhibitor for COVID-19 drug candidate DOI

Nurul Ahillah,

Mohamad Amin, Sri Rahayu Lestari

и другие.

AIP conference proceedings, Год журнала: 2023, Номер 2634, С. 020076 - 020076

Опубликована: Янв. 1, 2023

Views Icon Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Twitter Facebook Reddit LinkedIn Tools Reprints and Permissions Cite Search Site Citation Nurul Ahillah, Mohamad Amin, Sri Rahayu Lestari; In silico analysis of white turmeric cholorogenic acid compound as angiotensin-converting Enzyme-2 (ACE2) inhibitor for COVID-19 drug candidate. AIP Conference Proceedings 24 January 2023; 2634 (1): 020076. https://doi.org/10.1063/5.0111657 Download citation file: Ris (Zotero) Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Dropdown Menu input auto suggest filter your All ContentAIP Publishing PortfolioAIP Advanced |Citation

Язык: Английский

Процитировано

0
Inhibitors of the Oncogenic PA2G4-MYCN Protein-Protein Interface DOI Open Access

Hassina Massudi,

Jie-Si Luo, Jessica K. Holien

и другие.

Cancers, Год журнала: 2023, Номер 15(6), С. 1822 - 1822

Опубликована: Март 17, 2023

MYCN is a major oncogenic driver for neuroblastoma tumorigenesis, yet there are no direct inhibitors. We have previously identified PA2G4 as protein-binding partner of and drive tumorigenesis. A small molecule known to bind PA2G4, WS6, significantly decreased tumorigenicity in TH-MYCN mice, along with the inhibition interactions. Here, we number novel WS6 analogues, 80% structural similarity, used surface plasmon resonance assays determine their binding affinity. Analogues #5333 #5338 showed towards human recombinant PA2G4. Importantly, demonstrated 70-fold lower toxicity normal myofibroblasts compared WS6. Structure-activity relationship analysis that 2,3 dimethylphenol was most suitable substituent at R1 position. Replacing trifluoromethyl group on phenyl ring R2 position, bromine or hydrogen atom, increased difference between efficacy against cells myofibroblast toxicity. The analogues inhibited cell phenotype vitro, part through effects apoptosis, while anti-cancer required both expression. Collectively, chemical PA2G4-MYCN by represents first-in-class drug discovery which may implications other MYCN-driven cancers.

Язык: Английский

Процитировано

0