Molecular docking, Group Interaction Contribution (GIC), and ADMET studies on the role of surfactants in improving the permeability and solubility of mitoxantrone.

CONTEXT: Mitoxantrone (MTX) is an anticancer drug characterized by its hydrophobicity and low bioavailability, which can be increased by adding adjuvants to the formulation, such as surfactants (SFT). They can interact effectively with drugs, improve solubility and permeability, and stabilize them, thanks to unique properties such as amphiphilicity, adsorption, and micellization. METHODS: This novel in silico study explores the intermolecular interactions between 128 surfactants and the chemotherapeutic anticancer agent "Mitoxantrone", using molecular docking and the GIC approach. First, the MTX-SFT complexes were generated through ligand-ligand docking, showing various interactions (e.g., H-bond, π-π stacking, Pi-Alkyl). Next, to evaluate the effectiveness of these structural combinations in inhibiting Topoisomerase IIα (PDB ID: 1ZXM), a series of docking studies was performed to assess a variety of binding poses and ultimately determine the top-scoring complexes and the best binding poses. RESULTS: The docking results revealed that, among the 128 complexes generated, 70 complexes exhibited good Binding Energy (∆G) ranging from -34,727 to -48.116 kJ/mol. The ADMET evaluation was performed on the complexes with the highest affinity, identifying the top 33 complexes with favorable pharmacokinetic properties. Among the MTX-SFT complexes - that have top-scoring and exhibited greater inhibitory activity against topoisomerase IIα than other modified forms are MTX-Sodium Ricinoleate, MTX-Magnesium Ricinoleate, MTX-Glyceryl Laurate (Monolaurin), MTX-Sodium Lauroyl Sarcosinate, MTX-Sphingosine-1-Phosphate, MTX-Glyceryl Caprate, and MTX-Sorbitan Monolaurate (Span20). Additionally, the (GIC) approach demonstrated a strong relationship between molecular structure and interaction efficiency. The linear model yielded an AARD% of 1,4247% (R2 = 0,852), and the non-linear model provided an AARD% of 0,8993% (R2 = 0,996), confirming that SFT can form more effective complexes with MTX. CONCLUSIONS: This study emphasizes the potential of surfactants to improve the properties of Mitoxantrone and enhance its therapeutic efficacy against breast cancer, paving the way for the development of more effective and safer anticancer therapies.