Comprehensive Molecular Docking and Molecular Dynamics Reveal Inhibitors of HER2 L755S, T798I, and T798M based on a Large Database of Curcumin Derivatives

Document Type : Research Articles

Authors

1 Graduate School of Master of Pharmaceutical Sciences, Faculty of Pharmacy, Universitas Gadjah Mada, Indonesia.

2 Translational Research Center in Oncohaematology, Department of Cell Physiology and Metabolism, Faculty of Medicine, University of Geneva, Indonesia.

3 Laboratory of Medicinal Chemistry, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada, Sekip Utara, Sleman, Yogyakarta Indonesia.

Abstract

Objective: This study presents a methodology employing virtual screening to identify curcumin derivatives with selective affinity for the HER2 mutations L755S, T798I, and T798M. Methods: Curcumin derivatives were retrieved from the ChEMBL database and filtered using KNIME. HER2 mutations were modeled in silico using MOE software with PDB ID 3RCD. Molecular docking and dynamics simulations were conducted to screen high-affinity compounds and evaluate binding interactions. Result: From 505 curcumin derivatives, the RDKit module implemented in KNIME successfully filtered 317 compounds. Subsequent molecular docking against wild-type HER2 identified 100 curcumin derivatives with low docking scores, among which the top 20 compounds exhibited better binding affinities than Lapatinib. Further molecular docking screening against the three HER2 mutations identified five lead compounds with the lowest docking scores. Molecular docking and molecular dynamics simulation revealed critical binding interactions with residues essential for kinase domain stability. Chemical structural analysis revealed key modifications, such as geranyl and tripeptide modifications. CHEMBL3758656 and CHEMBL3827366, two curcumin derivatives, demonstrated consistent binding across HER2 mutations and a favorable ADMET profile. Conclusion: This study successfully identified CHEMBL3758656 and CHEMBL3827366 as promising HER2 inhibitors through comprehensive virtual screening. Their high binding affinity against L755S, T798I, and T798M mutations and favorable ADME and toxicity properties underscore their potential as alternative therapeutics for HER2-positive breast cancer.

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Asian Pacific Journal of Cancer Prevention
Volume 27, Issue 1
January 2026
Pages 265-279

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History

  • Receive Date: 25 June 2025
  • Revise Date: 15 August 2025
  • Accept Date: 18 January 2026

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