In Silico Evaluation of Doxorubicin and Levofloxacin as Multi-Isoform PI3K Inhibitors: Molecular Docking, Molecular Dynamics Simulations, and MM/PBSA Analysis
Abstract
The phosphoinositide‑3‑kinase (PI3K) pathway is a key regulator of cancer cell proliferation, survival, metabolism, and therapeutic resistance. Because PI3Kα, PI3Kβ, and PI3Kγ contribute differently to oncogenic signaling, strategies that assess ligands capable of engaging multiple isoforms are of increasing interest. We investigated the potential of two clinically established drugs—doxorubicin and levofloxacin—to interact with PI3K isoforms using a comprehensive in‑silico computational workflow. Protein structures of PI3Kα, PI3Kβ, and PI3Kγ were subjected to a refined docking using AutoDock 4.2. The top‑ranked complexes were evaluated through 100‑ns molecular dynamics simulations using GROMACS. Post‑simulation analyses included Root mean square deviation (RMSD), Root mean square fluctuation (RMSF), radius of gyration (Rg), solvent‑accessible surface area, hydrogen‑bond evaluation, principal component analysis, free‑energy landscape mapping (FEL), MM/PBSA binding‑energy calculations. Across all three PI3K isoforms, doxorubicin demonstrated stronger docking affinities, more stable binding poses, and consistently lower‑energy conformational states compared to levofloxacin. Molecular dynamics confirmed that doxorubicin maintained compact and stable interactions, supported by lower RMSD values, higher buried SASA, and a greater number of persistent hydrogen bonds. MM/PBSA results further indicated more favorable binding free energies for doxorubicin across all isoforms.…
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