N. V. Khmil, V. G. Kolesnikov

Model study of the protein-ligand binding in the development of hypersensitivity to folic acid and its analogs

  • General Physics and Astronomy
  • Physics and Astronomy (miscellaneous)

Folic acid (FA) plays a vital role in various metabolic processes, including synthesis and repair of DNA, cell division, the production of red blood cells, and fetal development. However, hypersensitivity to FA and its analogs can occur, leading to various symptomatic manifestations, including shortness of breath, skin rashes, itching, hives, swelling, gastrointestinal disturbances, tachycardia, and anaphylaxis. The mechanism of hypersensitivity to FA and its analogs is not well understood. However, it is known that human serum albumin (HSA) serves as a major pharmacokinetic effector for many substances and drugs, including FA and its analogs such as 5-methyltetrahydrofolic acid (5-MTHF), tetrahydrofolic acid (THFA), and methotrexate (MTX). HSA can interact with these compounds, affecting their distribution and metabolism. The study aimed to study the energetic and topological characteristics of the non-covalent complexes formed between HSA and FA and its analogs in order to obtain more complete information about the potential mechanisms involved in hypersensitivity reactions. Molecular docking was applied to search for the most energetically favorable conformations of the protein-ligand complexes and score the geometries based on their lowest binding energy. The 3D structure of HSA (PDB ID: 1AO6) was used as the docking target, which was obtained from the protein database. The structures of the ligands (FA, 5-MTHF, THFA, and MTX) were downloaded from PubChem, an open chemistry database at the National Institutes of Health. The surface area, volume, and depth of the binding pocket were determined using Proteins Plus. The identification of non-covalent interactions between HSA and the ligands was carried out using the PoseView and DoGSiteScorer web tools. It has been demonstrated that hydrophobic interactions and hydrogen bonds predominantly stabilize all the studied HSA-ligand complexes. Molecular docking analysis revealed that HSA binds the ligands within subdomains IB, IIA, and IIIA, with a binding energy of less than –10.0 kcal/mol. Identifying specific binding sites within the new antigen structures (the complex of HSA with the ligands) can be valuable in determining the energetically favorable binding of epitopes from these antigens to the active sites of IgE antibodies or immune cell receptors.

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