Exploring FDA-Approved Drugs Against HER2⁺ Breast Cancer: A Comprehensive In-Silico Identification of Lurtotecan as a Promising Candidate

Abstract

HER2 (human epidermal growth factor receptor 2) is a critical oncogenic driver in aggressive breast cancers (BC) and remains an important target for therapeutic intervention. Although targeted therapies such as trastuzumab deruxtecan have shown remarkable efficacy, identifying alternative HER2 inhibitors is essential to overcome resistance and expand treatment options. In this study, an integrated in-silico drug repurposing strategy combining pharmacophore-based virtual screening of the DrugBank database, molecular docking, prime Molecular Mechanics Generalized Born Surface Area (MM/GBSA), molecular dynamics (MD) simulations, and post-MD MM/GBSA free energy calculations was applied to identify FDA-approved compounds with potential HER2+ inhibitory activity. The SwissSimilarity screening of the DrugBank database using the pharmacophore-based screening method retrieved fourteen (14) compounds structurally similar to trastuzumab deruxtecan, with similarity scores between 0.352 and 0.751. Further, molecular docking performed using PyRx revealed strong binding affinities ranging from -7.9 to -11.6 kcal/mol, identifying Exatecan (-11.6 kcal/mol), Gimatecan (-10.9 kcal/mol), and Lurtotecan (-10.6 kcal/mol) as top candidates. The clinically approved HER2-targeted drug Trastuzumab Deruxtecan was used as a reference compound for benchmarking the binding interactions, exhibiting a binding affinity of -9.9 kcal/mol. Moreover, prime MM/GBSA calculations supported these findings, with binding free energies of -53.00 kcal/mol for trastuzumab deruxtecan and -45.84 kcal/mol for lurtotecan. MD simulations over 200 ns confirmed the conformational stability of the Lurtotecan-HER2 complex, demonstrating consistent root-mean-square deviation (RMSD) and root-mean-square fluctuations (RMSF) profiles, a stable radius of gyration (RoG), and hydrogen bonding (HB), indicating enhanced structural compactness. Post-MD simulation MM/GBSA analysis revealed a binding free energy of -26.13 ± 8.50 kcal/mol for Lurtotecan, which was comparable to -24.18 ± 6.21 kcal/mol for Trastuzumab Deruxtecan, indicating stable interactions with HER2. Functional enrichment analysis (GO and KEGG) revealed a significant association with oncogenic pathways such as “Pathways in cancer” (hsa05200), involving HER2, PIK3CA, and MTOR. Collectively, these integrative computational findings highlight lurtotecan as a promising candidate for repurposing against HER2+ BC and merit further in vitro and in vivo evaluation.