Identification of novel c-Kit inhibitors from natural sources using virtual screening and molecular dynamics simulations

Abstract

The Mast/Stem cell growth factor receptor Kit (c-Kit), a Proto-oncogene c-Kit, is a tyrosine-protein kinase involved in cell differentiation, proliferation, migration, and survival. Its role in developing certain cancers, particularly gastrointestinal stromal tumors (GISTs) and acute myeloid leukemia (AML), makes it an attractive therapeutic target. Several small molecule inhibitors targeting c-Kit have been developed and approved for clinical use. Recent studies have focused on identifying and optimizing natural compounds as c-Kit inhibitors employing virtual screening. Still, drug resistance, off-target side effects, and variability in patient response remain significant challenges. From this perspective, phytochemicals could be an important resource for discovering novel c-Kit inhibitors with less toxicity, improved efficacy, and high specificity. This study aimed to uncover possible c-Kit inhibitors by utilizing a structure-based virtual screening of active phytoconstituents from Indian medicinal plants. Through the screening stages, two promising candidates, Anilinonaphthalene and Licoflavonol, were chosen based on their drug-like features and ability to bind to c-Kit. These chosen candidates were subjected to all-atom molecular dynamics (MD) simulations to evaluate their stability and interaction with c-Kit. The selected compounds Anilinonaphthalene from Daucus carota and Licoflavonol from Glycyrrhiza glabra showed their potential to act as selective binding partners of c-Kit. Our results suggest that the identified phytoconstituents could serve as a starting point to develop novel c-Kit inhibitors for developing new and effective therapies against multiple cancers, including GISTs and AML. The use of virtual screening and MD simulations provides a rational approach to discovering potential drug candidates from natural sources.

Communicated by Ramaswamy H. Sarma

Keywords:

• Tyrosine-protein kinase c-Kit
• gastrointestinal stromal tumors
• plant-based compounds
• anilinonaphthalene
• licoflavonol
• drug discovery

Acknowledgements

The authors extend their appreciation to the Deanship of Scientific Research at Jouf University for funding this work through research grant No (DSR-2021-01-0203).

Author’s contributions

Abdelbaset Mohamed Elasbali: conceptualization, writing-review and editing; Waleed Abu Al-Soud: visualization, data analysis, software, writing-review and editing, software; Elyasa Mustafa Elfaki: data validation, data analysis, writing-review and editing; Hamad H. Alanazi: conceptualization, data analysis, editing, data curation, writing-original draft; Bandar Alharbi: visualization, software, data validation, writing-review and editing; Salem Hussain Alharethi: data validation, data analysis, writing-review and editing; Khalid Anwer: data validation, software, project administration, writing-original draft, data duration, investigation; Taj Mohammad: methodology, investigation, writing-review and editing; Md. Imtaiyaz Hassan: data curation, supervision, visualization, writing-review and editing, formal analysis, project administration, writing-original draft.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

All data analyzed during this study are included in this manuscript and Supplementary Materials are attached to this paper. The raw data generated during this study will be available upon request.

Additional information

Funding

This work is supported by the Indian Council of Medical Research (Grant No. ISRM/12(22)/2020).