Virtual Screening Targeting Dimerization Signals of Two Mycoplasma HU Proteins Revealed Different Types of Inhibitors Interacting with Common Binding Determinants

摘要

DNA-Binding HU proteins are critical to the maintenance of the nucleoid structure and are promising pharmacological targets for the design of new antibiotics. The virtual screening for low-molecular-weight compounds capable of specifically interacting with the dimerization signals of two mycoplasma HU proteins was performed. The stability of target protein-ligand complexes was evaluated by molecular dynamics simulation. An analysis of the amino-acid environment of the ligands shows that inhibitors targeting the conserved amino-acid sequence, the so-called dimerization signal, which is involved in the formation of HU dimers and the maintenance of their stability and is located in an interdimer beta-sheet, have the second binding site in the alpha-helical domain. The binding determinants of inhibitors at the dimer interfaces of the proteins are identical and are independent of the amino-acid sequence. Consequently, HU proteins have two sites for the formation of the dimer interface, which should be taken into account in the design of inhibitors of dimerization.