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Discovery of novel natural compounds for inhibiting JNK signaling in cancer: Multi-step virtual screening, MM-GBSA calculations, and molecular dynamics simulations

Article

Last updated: 29 Mar 2025

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Subjects

-

Tags

Pharmaceutical Chemistry

Abstract

Human c-Jun N-terminal kinase 1 (JNK1) is a cytosolic kinase within the mitogen-activated protein kinase family, pivotal in intracellular signal transduction cascades. Overexpression of JNK1 implicated in various cancers. Despite some JNK1 inhibitors progressing to clinical trials, none have gained market approval, underscoring the urgent need for new candidates. Computer-aided drug design lowers the expenses and time required for drug development. Rough estimates indicate that computational processes take less than one-third of the usual time and cost. This research employs diverse in silico screening methods to rapidly identify inhibitors for JNK1 associated with cancer. Specifically, we employed pharmacophore modeling on the bound ligand of JNK1 protein to identify essential pharmacophoric features crucial for discovering potential inhibitors. These features were screened against 449,008 natural compounds sourced from the SN3 database. The identified compounds underwent docking and MM-GBSA calculations. Two compounds (SN0239242 and SN0263268) exhibited superior MM-GBSA binding affinity compared to the bound ligand, with values of -69.22, -62.2, and -57.68 kcal/mol, respectively. These compounds were subjected to 100 ns molecular dynamics experiments and exhibited stable interactions. Natural compounds from these in silico studies showed promising anticancer potential as JNK1 inhibitors and could be prioritized for future experimental validation.

DOI

10.21608/ejchem.2024.297681.9866

Keywords

Cancer, JNK1, Natural compounds, docking, Molecular Dynamics, health and wellbeing, Drug Discovery

Authors

First Name

Abdulrahim A.

Last Name

Alzain

MiddleName

-

Affiliation

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Gezira, Sudan

Email

abdulrahim.altoam@gmail.com

City

Gezira

Orcid

-

First Name

Rayan

Last Name

Yousif

MiddleName

-

Affiliation

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Gezira, Sudan

Email

ryanyosife222@gmail.com

City

-

Orcid

-

First Name

Mohammed A.

Last Name

Almogaddam

MiddleName

-

Affiliation

Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Gezira, Sudan

Email

almogaddamma@gmail.com

City

-

Orcid

-

First Name

Hazem G. A.

Last Name

Hussein

MiddleName

-

Affiliation

General Medicine Practice Program, Batterjee Medical College, Jeddah 21442, Saudi Arabia

Email

hazemgamal2005@gmail.com

City

-

Orcid

-

First Name

Ehda Ahmad

Last Name

Awad

MiddleName

-

Affiliation

Prince Mohammed Bin Abdulaziz Hospital-Al Madinah Al Munawarah-NGHA, Ministry of National Guard Health Affairs, Al Madinah Al Munawarah 41511, Saudi Arabia

Email

ehdaa.ahmad.awadh@gmail.com

City

-

Orcid

-

First Name

Ahmed Mohammad

Last Name

Alraddadi

MiddleName

-

Affiliation

Prince Mohammed Bin Abdulaziz Hospital-Al Madinah Al Munawarah-NGHA, Ministry of National Guard Health Affairs, Al Madinah Al Munawarah 41511, Saudi Arabia

Email

alraddadi205@gmail.com

City

-

Orcid

-

First Name

Shaimaa G. A.

Last Name

Mohamed

MiddleName

-

Affiliation

Faculty of Dentistry, British University, El Sherouk City, Suez Desert Road, Cairo 11837, Egypt

Email

shaimaag1973@gmail.com

City

-

Orcid

-

First Name

Abdullah L.

Last Name

Alalawi

MiddleName

-

Affiliation

Pharmaceutical Care Services, King Salman Medical City, MOH, Al Madinah Al Munawwarah 11176, Saudi Arabia

Email

abdullahalalawi96@gmail.com

City

-

Orcid

-

First Name

Gamal A.

Last Name

Mohamed

MiddleName

-

Affiliation

Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia

Email

gahussein@kau.edu.sa

City

-

Orcid

-

First Name

Abdulmajeed M.

Last Name

Althubyani

MiddleName

-

Affiliation

Anesthesia Department, King Fahad hospital, MOH, Al Madinah Al Munawwarah, Saudi Arabia

Email

adalthubyani@moh.gov.sa

City

-

Orcid

-

First Name

Sabrin

Last Name

Ibrahim

MiddleName

R. M.

Affiliation

Preparatory Year Program, Batterjee Medical College, Jeddah 21442, Saudi Arabia

Email

sabrin.ibrahim@bmc.edu.sa

City

Jeddah

Orcid

0000-0002-6858-7560

Volume

68

Article Issue

5

Related Issue

54251

Issue Date

2025-05-01

Receive Date

2024-06-14

Publish Date

2025-05-01

Page Start

23

Page End

35

Print ISSN

0449-2285

Online ISSN

2357-0245

Article File

EJCHEM_Volume 68_Issue 5_Pages 23-35.pdf

PDF . 2.0MB

Link

https://ejchem.journals.ekb.eg/article_379227.html

Detail API

http://journals.ekb.eg?_action=service&article_code=379227

Order

379,227

Type

Original Article

Type Code

297

Publication Type

Journal

Publication Title

Egyptian Journal of Chemistry

Publication Link

https://ejchem.journals.ekb.eg/

MainTitle

Discovery of novel natural compounds for inhibiting JNK signaling in cancer: Multi-step virtual screening, MM-GBSA calculations, and molecular dynamics simulations

Details

Type

Article

Created At

09 Mar 2025