Molecular docking and dynamics analysis of flavonoids from Retama monosperma with drug-resistant GIST mutations

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Title	*Molecular docking and dynamics analysis of flavonoids from Retama monosperma* with drug-resistant GIST mutations**
Authors	Kaoutar El Khattabi^1,*, Jihane Akachar¹, Sanaa Lemriss², Rachid El Jaoudi¹ & Fouad Zouaidia^1,3
Affiliation	¹Medical Biotechnology Laboratory, Rabat Medical and Pharmacy School, Mohammed V University in Rabat, Rabat, Morocco; ²Department of Biosecurity PCL3, Laboratory of Research and Medical Analysis of the Fraternal of Gendarmerie Royale, Rabat, Morocco; ³Pathology Department, Ibn Sina University Hospital, Rabat, Morocco; *Corresponding author
Email	Kaoutar El khattabi - E-mail: kaoutar_elkhattabi3@um5.ac.ma Jihane Akachar - E-mail: jihane.akachar@gmail.com Sanaa Lemriss - E-mail: slemriss@lram-fgr.ma Rachid El Jaoudi - E-mail: eljaoudi_rachid@yahoo.fr Fouad Zouaidia - E-mail: zouaidiapathology@gmail.com
Article Type	Research Article
Date	Received September 1, 2024; Revised September 30, 2024; Accepted September 30, 2024, Published September 30, 2024
Abstract	Gastrointestinal stromal tumors (GISTs), the most prevalent mesenchymal tumors of the gastrointestinal tract, are predominantly driven by activating mutations in receptor tyrosine kinases such as c-Kit and PDGFRα. Resistance to tyrosine kinase inhibitors (TKIs) poses a substantial therapeutic challenge, underscoring the need for novel treatments. Consequently, investigating the potential of natural compounds, specifically flavonoids from Retama monosperma, known for their diverse bioactivities, is of significant interest. Molecular docking and simulations revealed that Luteolin exhibited high binding affinities for PDGFRα (-8.1 kcal/mol) and c-KIT (-9.6 kcal/mol), comparable to Avapritinib and Sunitinib. The compound demonstrated favorable ADMET properties and formed notable hydrogen bonds and hydrophobic interactions with key residues in both targets. Molecular dynamic simulation over 100 ns revealed stable complexes with consistent RMSD and RMSF values. Additionally, Luteolin showed strong binding affinities to the resistant mutations c-Kit (D816H) and PDGFRα (T674I), with enhanced stability. These findings suggest that Luteolin has significant potential as a dual inhibitor and offers a promising alternative to conventional TKIs for addressing GIST resistance.
Keywords	Gastrointestinal stromal tumors, Retama monosperma, flavonoids, molecular docking, molecular dynamics simulations.
Citation	Khattabi et al. Bioinformation 20(9): 966-973 (2024)
Edited by	P Kangueane
ISSN	0973-2063
Publisher	Biomedical Informatics
License	This is an Open Access article which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. This is distributed under the terms of the Creative Commons Attribution License.