Exploring Camptothecin Derivatives from the Chinese Tree of Camptotheca acuminata as Breast Cancer Protease Inhibitors: Insights from Multi-Scale Computational Analysis

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Background Breast cancer is a highly prevalent and lethal type of cancer that affects women worldwide. Aims This study aimed to explore active alkaloid-induced camptothecin (CPT) derivatives as efficacious agents for the treatment of triple-negative breast cancer (TNBC) by molecular docking simulation. Methods First of all, the DFT method from Material Studio 8.0 was executed to optimize ligands and evaluate the quantum descriptors. The binding affinities of a series of twelve ligands with human topoisomerase IIα (5GWK) and p53 (4OQ3) were assessed. A protein data bank (PDB) was used to obtain the 3D structure of PDB ID: 5GWK (human topoisomerase II α in complex with DNA and etoposide) and PDB ID: 4OQ3 (Tetra-substituted imidazoles as a new class of inhibitors of the p53-MDM2 interaction). SwissADME and admetSAR - 2.0 were used to perform the absorption, distribution, metabolism, excretion, and toxicity (ADMET). Molecular dynamic simulations were conducted using the Desmond software suite. Results Ligand L05 emerged as a standout, demonstrating the highest binding affinity for both proteins, thereby positioning itself as a potential dual-targeting therapeutic agent. Notably, all ligands exhibited a propensity for higher binding affinity with 5GWK over p53. Pharmacokinetic profiling further delineated the drug-like attributes of the ligands, which included a molecular weight spectrum of 372.54 to 420.65 g/mol, rotatable bonds ranging from one to four, hydrogen bond acceptors between four to six, and hydrogen bond donors limited to zero or one, which satisfied the drug-likeness properties. Conclusion The comparative analysis of binding energies obtained from PyRx and Glide molecular docking simulations of twelve ligands with human topoisomerase IIα (5GWK) and p53 (4OQ3) provides insights into the efficacy of these computational tools in computer-aided drug discovery for TNBC.