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

Alzain, Abdulrahim A.; Yousif, Rayan; Almogaddam, Mohammed A.; Hussein, Hazem G. A.; Awad, Ehda Ahmad; Alraddadi, Ahmed Mohammad; Mohamed, Shaimaa G. A.; Alalawi, Abdullah L.; Mohamed, Gamal A.; Althubyani, Abdulmajeed M.; Ibrahim, Sabrin R. M.

doi:10.21608/ejchem.2024.297681.9866

	Discovery of novel natural compounds for inhibiting JNK signaling in cancer: Multi-step virtual screening, MM-GBSA calculations, and molecular dynamics simulations
Egyptian Journal of Chemistry
Articles in Press, Accepted Manuscript, Available Online from 10 September 2024
Document Type: Original Article
DOI: 10.21608/ejchem.2024.297681.9866
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Authors
Abdulrahim A. Alzain¹; Rayan Yousif¹; Mohammed A. Almogaddam¹; Hazem G. A. Hussein²; Ehda Ahmad Awad³; Ahmed Mohammad Alraddadi³; Shaimaa G. A. Mohamed⁴; Abdullah L. Alalawi⁵; Gamal A. Mohamed⁶; Abdulmajeed M. Althubyani⁷; Sabrin R. M. Ibrahim ⁸
¹Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Gezira, Gezira, Sudan
²General Medicine Practice Program, Batterjee Medical College, Jeddah 21442, Saudi Arabia
³Prince Mohammed Bin Abdulaziz Hospital-Al Madinah Al Munawarah-NGHA, Ministry of National Guard Health Affairs, Al Madinah Al Munawarah 41511, Saudi Arabia
⁴Faculty of Dentistry, British University, El Sherouk City, Suez Desert Road, Cairo 11837, Egypt
⁵Pharmaceutical Care Services, King Salman Medical City, MOH, Al Madinah Al Munawwarah 11176, Saudi Arabia
⁶Department of Natural Products and Alternative Medicine, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
⁷Anesthesia Department, King Fahad hospital, MOH, Al Madinah Al Munawwarah, Saudi Arabia
⁸Preparatory Year Program, Batterjee Medical College, Jeddah 21442, Saudi Arabia
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.
Keywords
Cancer; JNK1; Natural compounds; Docking; Molecular Dynamics; Health and wellbeing; Drug discovery


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