Theoretical models to predict the inhibitory effect of ligands of sphingosine kinase 1 using QTAIM calculations and hydrogen bond dynamic propensity analysis

Abstract

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.

Design of new quinolin-2-one-pyrimidine hybrids as sphingosine kinases inhibitors

“…More recently, we expanded this study and specific inhibitors of SphK2 with potential antiinflammatory properties were arisen [17]. In addition to the useful information about the structural characteristics of SphK1, we also found excellent correlations between theoretical calculations and experimental data [18]. In the search of more potent SphK1 inhibitors, in this study we have used a different strategy.…”

Evaluating the conformational space of the active site of D2 dopamine receptor. Scope and limitations of the standard docking methods

“…[64] This type of calculations has been used in recent works since it ensures a reasonable compromise between the wave function quality required to obtain reliable values of ρ(r) and the computer power available, considering the extension of the system in study. [15,[65][66][67][68]…”

“…A study carried out by our research group on flexible ligands acting as sphingosine kinase 1 (SphK1) inhibitors showed that not only docking calculations have limitations, but also molecular dynamics simulations have limitations for evaluating this type of complexes. [ 15 ] Our results show that it is necessary to increase the number of simulations and perform clustering processes in order to be able to evaluate this type of L‐R complex satisfactorily. In contrast, in the case of type (i) L‐R complexes, docking calculations combined with relatively simple MD simulations are highly satisfactory and allow us to obtain good correlations between theoretical results and activity data obtained from experimental measurements.…”

Quinolin-2-one-pyrimidine Hybrids Acting as Potent Reversal Agents on the P-gp-mediated Multidrug Resistance: Insights into Structure-activity Relationships and the Binding Mode

“…QTAIM calculations are very useful tools for evaluating accurately and in detail the molecular interactions which stabilize ligand-receptor complexes 30 and can be used successfully in different biological systems [31][32][33][34][35] . In order to analyze the molecular interactions stabilizing the complexes of the target molecules and P-gp more quantitatively and with more detail, QM/MM calculations were performed, choosing the most representative complexes of the series.…”