Computer-aided structure-based optimization of 4,5,6,7- tetrahydrobenzo[d]thiazole-2,6-diamine derivatives as DNA gyrase B inhibitors

GUTIÉRREZ, LUCAS; MARCELA VETTORAZZI; JAKA DERNOV?EK; MARTINA DURCIK; LUCIJA PETERLIN MA?Ič; TIHOMIR TOMA?Ič; ENRIZ, RICARDO DANIEL

NEW JOURNAL OF CHEMISTRY

ROYAL SOC CHEMISTRY

Lugar: CAMBRIDGE; Año: 2023

1144-0546

Here we report a theoretical-experimental study of 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine derivatives that act inhibitors of bacterial DNA gyrase B (GyrB). A comprehensive analysis of the various molecular interactions that stabilizethe molecular complexes was performed using combined theoretical techniques. Our results showed that QTAIM(Quantum Theory of Atoms In Molecules) calculations are a very useful tool for quantitatively describing the molecularinteractions to determine which amino acids interact with the ligands. Moreover, our simulations have shown that thisapproach not only provides a detailed description of the different affinities of the ligands, but also has predictive power forcompounds that have not yet been synthesized. In fact, we have synthesized and tested three new DNA gyrase inhibitors,two of which exhibit significant inhibitory activity. One of them binds spatially differently from known GyrB inhibitorsbecause its 3-oxopropanoic acid moiety is oriented toward a previously unexplored subsite of the binding pocket.