Based on the structural data about the binding mode of AMP-PNP molecule to human topo IIα, we designed a two stage virtual screening campaign combining structure-based pharmacophores and molecular docking, identifying in the first stage several mono-substituted 9H-purine compounds and a novel class of 1H-pyrazolo[3,4]pyrimidine inhibitors of the htIIα. In the second stage, bi-substituted analogues with improved properties for cell activity were discovered. Compounds from both classes were shown to inhibit htIIα-mediated decatenation and surface plasmon resonance (SPR) experiments confirmed binding of these two compounds on the htIIα ATPase domain. Proposed complexes and interaction pattern between compounds and htIIα were further analyzed in MD simulation studies. Two compounds identified in the second stage showed promising anticancer activities in hepatocellular carcinoma HepG2 and breast cancer MCF-7 cell lines.
COBISS.SI-ID: 5618714
Starting from our discovered 4-amino-1,3,5-triazine inhibitors of human topoisomerase IIα we initiated an in silico design study of a focused library of 2,4,6-trisubstituted-1,3,5-triazines to optimize the series. 6-substituted-4-(benzylthio)-1,3,5-triazin-2(1H)-ones which were identified as novel topoIIα inhibitors. The most active compound was able to inhibit the human topo IIα-mediated DNA decatenation and did not induce double-stranded breaks. Furthermore it inhibited the cleavage reaction induced by etoposide showing its inhibition step is in the early stages of topoII catalytic cycle. Binding studies using microscale thermophoresis (MST) established binding of 1,3,5-triazin-2(1H)-one compound to the htIIα ATPase domain, confirming for the first time the binding of a monocyclic catalytic inhibitors to the htIIα ATPase domain. The discovered 6-substituted-4-(benzylthio)-1,3,5-triazin-2(1H)-ones represent the first validated monocyclic class of catalytic inhibitors that bind to the ATP binding site and have the potential for hit to lead development of a monocyclic series of catalytic inhibitors of human DNA topoisomerase IIα.
COBISS.SI-ID: 3886961
In the field of antibacterial drug design we extended the knowledge of the class of furan-based benzene-1,3-dicarboxylic acid derivatives by first showing multiple MurC–MurF ligase inhibition for representatives of the series. Steady-state kinetics studies on the MurD enzyme were performed for compound 1, suggesting a competitive inhibition with respect to ATP. To the best of our knowledge the studied compound represents the first ATP-competitive MurD inhibitor reported to date with concurrent multiple inhibition of all four Mur ligases (MurC–MurF). Based on the obtained MD data novel furan-based benzene monocarboxylic acid derivatives exhibiting multiple Mur ligase (MurC–MurF) inhibition with predominantly superior ligase inhibition over the original series, were discovered and for selected compounds promising antibacterial activity against S. aureus was shown.
COBISS.SI-ID: 5677082
Acetaminophen (APAP) forms some reactive metabolites that can react with DNA. APAP is a potentially genotoxic drug and is classified as a Group 3 drug according to International Agency for Research on Cancer (IARC). One of the possible mechanisms of APAP genotoxicity after long term of use is that its reactive the quinone imine (QI) metabolite of acetaminophen (NAPQI), can chemically react with DNA after glutathione (GSH) depletion. A quantum chemical study of the reactions between the NAPQI and deoxyguanosine (dG) or GSH was performed. Activation energies ([delta]G) for the reactions associated with the 1, 4-Michael addition were calculated on the M062X/6-311++G(d,p) level of theory. We modeled the reaction with dG as a multi-step process. The first step is rate-limiting ([delta]G=26.7 kcal/mol) and consists of formation of a C-N bond between the C3 atom of the QI moiety and the N7 atom of dG. The second step involves proton transfer from the C3 moiety to the nitrogen atom of the QI with [delta]G of 13.8 kcal/mol. The depurination reaction that a [delta]G of 25.7 kcal/mol. The calculated [delta]G for the nucleophilic attack of the deprotonated S atom of GSH on the C3 atom of the NAPQI is 12.9 kcal/mol. Therefore, the QI will react with GSH much faster than with DNA. Our study gives mechanistic insight into the genotoxicity of the APAP metabolite and will be useful for estimating the genotoxic potential of existing drugs with aQI moiety. Our results show that clinical application of APAP is safe, while in the case of severely depleted GSH levels APAP should be administred with caution.
COBISS.SI-ID: 3977585
Tolazamide belongs to a class of sulfonylurea derivatives used in the trearment of type 2 diabetes. With five known stable isomers, it exhibits the most pronounced tendency of polymorphism in this class of compounds. The present study uses a wide range of diffraction, spectroscopic and computational methods to elucidate the interactions governing the observed polymorphism. We found that subtle changes in nonbonding interactions may lead to major structural rearrangements. Perhaps the most crucial motif governing the structure are hydrogen bonds and their dynamics.
COBISS.SI-ID: 5775642