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Here we report a theoretical-experimental study of 4,5,6,7-tetrahydrobenzo[d]thiazole-2,6-diamine derivatives that act as inhibitors of bacterial DNA gyrase B (GyrB). A comprehensive analysis of the various molecular interactions that stabilize the 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 molecular interactions to determine which amino acids interact with the ligands. Moreover, our simulations have shown that this approach not only provides a detailed description of the different affinities of the ligands, but also has predictive power for compounds 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 inhibitors because its 3-oxopropanoic acid moiety is oriented toward a previously unexplored subsite of the binding pocket. [ABSTRACT FROM AUTHOR]

We report an exhaustive conformational and electronic study on dopamine (DA) interacting with the D2 dopamine receptor (D2DR). For the first time, the complete surface of the conformational potential energy of the complex DA/D2DR is reported. Such a surface was obtained through the use of QM/MM calculations. A detailed study of the molecular interactions that stabilize and destabilize the different molecular complexes was carried out using two techniques: Quantum Theory of Atoms in Molecules computations and nuclear magnetic shielding constants calculations. A comparative study of the behavior of DA in the gas phase, aqueous solution, and in the active site of D2DR has allowed us to evaluate the degree of deformation suffered by the ligand and, therefore, analyze how rustic are the lock‐key model and the induced fit theory in this case. Our results allow us to propose one of the conformations obtained as the "biologically relevant" conformation of DA when it is interacting with the D2DR. [ABSTRACT FROM AUTHOR]

We report here the results of two theoretical models to predict the inhibitory effect of inhibitors of sphingosine kinase 1 that stand on different computational basis. The active site of SphK1 is a complex system and the ligands under the study possess a significant conformational flexibility; therefore for our study we performed extended simulations and proper clusterization process. The two theoretical approaches used here, hydrogen bond dynamics propensity analysis and Quantum Theory of Atoms in Molecules (QTAIM) calculations, exhibit excellent correlations with the experimental data. In the case of the hydrogen bond dynamics propensity analysis, it is remarkable that a rather simple methodology with low computational requirements yields results in excellent accord with experimental data. In turn QTAIM calculations are much more computational demanding and are also more complex and tedious for data analysis than the hydrogen bond dynamic propensity analysis. However, this greater computational effort is justified because the QTAIM study, in addition to giving an excellent correlation with the experimental data, also gives us valuable information about which parts or functional groups of the different ligands are those that should be replaced in order to improve the interactions and thereby to increase the affinity for SphK1. Our results indicate that both approaches can be very useful in order to predict the inhibiting effect of new compounds before they are synthesized. [ABSTRACT FROM AUTHOR]