#ftsz

Abstract— There is a large group of bacterial FtsZ inhibitors, the biological activity of which has been confirmed biochemically. However, the sites of protein-ligand interaction for most of them remain unknown, significantly complicating the further search and combinatorial design of FtsZ inhibitors. This study presents the results of bioinformatic analysis of bacterial FtsZ effectors targeting sites of 4-hydroxycoumarin binding (BP1 and BP2). New data based on original results of pharmacophore screening, chemoinformatics, molecular docking, molecular dynamics simulations, AI-predictions, etc., are presented. The object of the study was a combined library of 379 compounds, formed based on revision of the structural database RCSB Protein Data Bank and biochemically proven FtsZ effectors from ChEMBL. Based on the results of a comprehensive study, 39 compounds were selected, of which 28 were identified as effectors of the sites BP1 and BP2, and another 11 as specific effectors of the site BP2 located in the BP2/IDC superpocket.

Abstract There is a large group of bacterial FtsZ inhibitors whose biological activity has been confirmed biochemically. However, the sites of protein–ligand interaction for most of them remain unknown, significantly complicating the further search and combinatorial design of FtsZ inhibitors. This study presents the results of bioinformatic analysis of bacterial FtsZ effectors, the interaction of which has been proven and documented in the ChEMBL database of biologically active molecules. With an integrated approach based on chemo- and bioinformatic methods and AI-based predictions, 23 inhibitors of nucleotide-binding site (NBS), as well as 16 new effectors of the interdomain cleft (IDC), were identified.

Abstract There are a significant number of inhibitors of the bacterial FtsZ protein with biochemically confirmed biological activity, at the same time, their binding sites remain unclear. This significantly complicates further combinatorial design, and, in the current study, the results of a computational search for effectors of the Inter-Domain Cleft (IDC) site are presented. The actual research was based on the results of pharmacophore screening using the Pharmit service and molecular docking with CCDC GOLD and iGEMDOCK programs. The objective group was a combined library of 379 compounds, which was designed based on revision of the structural database of the RCSB Protein Data Bank and compounds from the ChEMBL database, for which direct interaction with FtsZ has been proven biochemically. According to the results of pharmacophore search, docking, and structural analysis, 88 effectors of the IDC site were identified. One more curcumin compound has been identified as a potential IDC site effector.

Abstract The variability of the allosteric binding site pocket located in the interdomain cleft (IDC) of FtsZ proteins was investigated. The point-cloud models of the IDC site pockets were constructed based on 11 structures for the S. aureus complexes of FtsZ protein with 2,6-diflurobenzamides—OLQ, 9PC, OM8, OMW ZI1, ZI6, ZI7, and ZI9—which is currently deposed in the RCSB Protein Data Bank. Significant variability in the volume and shape of the IDC site pocket, formed under adaptation to the ligand, was demonstrated. Four main conformational states of the site pocket, resulting from ligand-protein fitting were selected. It indicates that the docking of the ligands into the IDC site of individual 3D-models of FtsZ protein molecules is not effective. It was concluded that virtual screening efficiency can be significantly improved by the use of an ensemble of molecular targets considering the conformational variability of the IDC site pocket of bacterial FtsZ protein.

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