Specificity of the Interactions of Folate-Based Vectors with Folate Receptor-α

The study explores the molecular-level binding of a set of vector ligands─folate, methotrexate, raltitrexed, pemetrexed, 5-methyltetrahydrofolate, and pteroyl ornithine─to the membrane-embedded folate receptor-α, a relevant target in cancer therapy. Statistical analysis of data from molecular dynamics simulations is performed to quantify the suitability of the ligands as constituents of active targeting drug delivery systems. The preferred binding modes of each ligand are identified and discussed in terms of ligand positioning and mechanism of binding. Interaction maps and structures of representative clusters highlight the key amino acid residues involved in the ligand-receptor complexes and provide clues for the attachment mechanism of the ligands. The results reveal that the complex formation is primarily driven by dispersion forces, particularly involving the pterin and aminobenzoate fragments, with additional stabilization from hydrogen bonds and electrostatics. Specific interaction patterns are identified for each ligand, which provide rationalization of the experimentally registered dissimilar behavior of the studied vectors toward the receptor. On the basis of the performed analyses, general guidelines for ligands to bind to the active site of the protein are formulated. Among the addressed ligands, only folate and raltitrexed comply with the requirements and bind sustainably to the receptor active site, outlining them as effective vectors for folate-based drug-delivery systems.