Stability of HIV-1 integrase-ligand complexes: The role of coordinating bonds

It is known that the HIV-1 integrase (IN) strand transfer inhibitors include the chelating fragments forming the coordinating bonds with two Mg2+ ions placed in the IN active site. The subject of the article is the role of these coordination bonds on stability of ligand–IN complexes. For this purpose, a set of ligand–IN complexes was investigated theoretically and experimentally. The theoretical model is based on the quantum-chemistry calculations of coordinating bonds geometry and energy. Solvent effects were taking into account using the implicit water model and the two-stage calculation scheme developed previously. For the experimental part of our study a set of the ligands was synthesized, and their IC50 values of IN inhibiting have been measured. It is shown that the main contribution to ligand–IN complexes stability is caused by the substitution of water molecules by the ligand in the first coordination sphere of two Mg2+ ions, and the change in the polarization energy of the bulk water. It is shown, that acid–base equilibrium and tautomeric forms of the ligands should be taken into account to improve the prediction ability of the theoretical estimations. All these factors are controlled by the chelating fragments of the ligands. It is demonstrated that our theoretical approach based on the consideration of the coordinating bonds allows to separate active ligands (inhibitors) from inactive ones.