Computational Investigation of KRAS regulatory targets through Berberine chloride in Lung cancer: Targeting upstream regulators of the MAPK Pathway

Arjun KR ¹, Shakeel Ahmed Adhoni ², Sunitha C Mesta ³, Baburao Gaddala ⁴, Shailasree Sekhar ⁵, Jeyarish V ¹, Varshitha BR ¹, Vindhya M ¹, Anil Kumar K M ⁶, Modugapalem Hemalatha ^7*, Kanthesh M Basalingappa ^1*

^1*Division of Molecular Biology, School of Life Sciences, JSS Academy of Higher Education & Research, Mysuru, Karnataka, India
²Division of Biological Science, School of Science and Technology, The University of Goroka, Eastern highland province, Papua New Guinea
³Department of Microbiology, School of Life Sciences, JSS Academy of Higher Education & Research, Mysuru, Karnataka, India
⁴Department of Chemical Engineering, School of Studies of Engineering and Technology, Guru Ghasidas Vishwavidyalaya, A Central University, Koni, Bilaspur, Chhattisgarh-495009, India
⁵Division of Biochemistry, School of Life Sciences, JSS Academy of Higher Education & Research, Mysuru, Karnataka, India
⁶Department of Environmental Science, School of Life Sciences, JSS Academy of Higher Education & Research, Mysuru, Karnataka, India
^7*Department of Biotechnology, Sri Venkateswara University, Tirupati-517502, India

---

ABSTRACT

KRAS-driven lung adenocarcinoma remains a major therapeutic challenge due to the protein's poor druggability and rapid activation cycle. Targeting upstream regulatory proteins that control KRAS activation and membrane localization represents a promising alternative strategy. Based on literature evidence, EGFR, SOS1, SHP2, and PDE6D were selected as key modulators involved in KRAS regulation in MAPK pathway signalling. Berberine chloride, a bioactive natural compound, has shown antitumour potential, but its molecular interactions with KRAS upstream regulators remain underexplored. To date, as per our knowledge, no paper has studied the molecular interaction of PDE6D and Berberine chloride to regulate KRAS protein.

Objective: In silico validation of the best binding protein target with Berberine chloride to regulate the KRAS mutation, using docking, MD simulations, and ADMET profiling.

Methods: The PubChem database was used to obtain the ligand structure. and the PDB was used for protein structure retrieval. Schrodinger is used to check the protein-ligand interactions, followed by Desmond for MD simulations. ADMET profiling was performed using SWISS ADME software.

Results: Berberine chloride exhibited favourable binding affinities towards all the upstream regulating targets of KRAS and the chaperone PDE6D. MD simulation confirmed the formation of a stable ligand-protein complex with low structural deviations and persistent interactions throughout the trajectory. RMSD, RMSF, and Rg analyses indicated robust structural stability, while ADMET predictions revealed acceptable absorption, distribution, metabolism, and toxicity profiles.

Conclusion: The overall results of Docking, MD simulations, and ADMET standardize the target protein as PDE6D chaperone as a better binding partner with Berberine chloride. The ADMET confirms the limitations of the drug in turn gives a strong validation to enhance the efficiency of the drug using nano-approaches.

Keywords: N/A.

Graphical Abstract:

[Graphical abstract placeholder]

How to cite this article: Arjun KR, Adhoni SA, Mesta SC, Gaddala B, Sekhar S, V J, BR V, M V, KM AK, Hemalatha M, Basalingappa KM., Computational Investigation of KRAS regulatory targets through Berberine chloride in Lung cancer: Targeting upstream regulators of the MAPK Pathway, In Vitro, and Ex Vivo Experimental Validation Supporting Adjunct Antifungal Therapy. Int J Drug Deliv Technol. 2026;16(3s): 544-561; DOI: 10.25258/ijddt.16.3s.72