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

VETTORAZZI, MARCELA; MENÉNDEZ, CINTIA; GUTIÉRREZ, LUCAS; ANDUJAR, SEBASTIÁN; APPIGNANESI, GUSTAVO; ENRIZ, RICARDO D.

J. COMPUT. AIDED MOL. RESIGN

SPRINGER

Año: 2018

0920-654X

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