Starting from the available structural information about the binding of the natural product inhibitor, clorobiocin, we identified a novel series of bithiazols inhibitors of DNA gyrase B with a low micromolar inhibitory activity, by implementing a two-step structure-based design procedure. This novel class of DNA gyrase inhibitors was extensively investigated by various techniques: Differential Scanning Fluorimetry (DSF), Surface Plasmon Resonance (SPR) and microscale thermophoresis (MST). The binding mode of the potent inhibitor was revealed by X-ray crystallography, confirming our initial in silico binding model.
COBISS.SI-ID: 4999450
Off-path simulation (OPS) technique, an extension of the well-established Replica Path Method (RPATh), was applied to compare the relative energy of the two by C-terminal domain of the MurD ligase closing motions generated by TMD simulations (Perdih et al. Proteins 2007). The first C-terminal domain closing process commenced from the experimental open structure in which this domain is located out-of plane to the N-terminal and central domains (open structure pdb:1EEH). In the second trajectory the conformational movement is confined to this plane only (open structure pdb:1E0D). The obtained results indicated that the C-terminal domain movement occurring from the out-of-plane starting structure is coupled with much higher energy changes compared to the motion of this domain within this plane which is more freely available to the enzyme.
COBISS.SI-ID: 4840730
Natural products are one of the most important sources of drug molecules now present in modern materia medica. Recently, when searching for novel lead compounds of natural origin, new integrated approaches were introduced that merge modern methods of separation, identification and biological assays with computer-assisted methods of drug design and virtual screening. This review is focused predominantly on the introduction of the computer-based approaches in this field. In addition, selected successful applications of the integrated approach in identifying novel natural products as lead compounds are presented that can be used also in antibacterial drug design.
COBISS.SI-ID: 4935450