In silico design and evaluation of a hydrophobic-hydrophilic combinatorial drug systems for targeted breast cancer therapy.

Combinatorial drugs are pharmacologically active compounds with molecular structures incorporating both hydrophobic and hydrophilic regions. These drugs utilize multiple mechanisms to enhance the therapeutic efficacy, overcoming the limitations of single drugs while providing a synergistic effect. In particular, Drug-drug conjugates act as versatile carriers, efficiently loading and delivering therapeutic agents to targeted sites, which improves treatment precision and outcomes. In this study, we present a computational analysis of a drug-drug conjugated small molecule (CHI-CAP) and its interaction with the PAK1 protein. Using Molecular Docking, MM/GBSA, Molecular Dynamics Simulations, MM/PBSA, DFT calculations, and ADME properties, computational methods were employed to investigate CHI, CAP, and conjugated CHI-CAP ligands. The docking studies revealed that the conjugated CHI-CAP ligand achieved a significantly enhanced docking score of -7.761 kcal/mol and formed multiple hydrogen bonds when bound with PAK1. Molecular Dynamics Simulations demonstrated that the CHI-CAP/PAK1 complex reached stability by 12 ns, maintaining a constant RMSD with an average value of 0.33 nm throughout the simulation. MMPBSA analysis further indicated that the binding free energy of the CHI-CAP/PAK1 complex suggests it is a more effective inhibitor compared to individual ligands. DFT analysis revealed that conjugated CHI-CAP has shown a favorable energy profile and specific binding interactions, enhancing its effectiveness in binding to and inhibiting PAK1 protein. ADME predictions confirmed that conjugated CHI-CAP ligand meets the acceptable parameters for human use. Based on these findings, the designed conjugated CHI-CAP drug-drug conjugate ligand shows promise as a potential therapeutic agent for Breast Cancer (BC), combining improved efficacy with targeted delivery capabilities.