Sodium or Not Sodium: Should Its Presence Affect the Accuracy of Pose Prediction in Docking GPCR Antagonists?

Abstract

The function of the allosteric sodium ion in stabilizing the inactive form of GPCRs has been extensively described in the past decades. Its presence has been reported to be essential for the binding of antagonist molecules in the orthosteric site of these very important therapeutical targets. Among the GPCR–antagonist crystal structures available, in most cases, the sodium ion could not be experimentally resolved, obliging computational scientists using GPCRs as targets for virtual screening to ask: “Should the sodium ion affect the accuracy of pose prediction in docking GPCR antagonists?” In the present study, we examined the performance of three orthogonal docking programs in the self-docking of GPCR antagonists to try to answer this question. The results of the present work highlight that if the sodium ion is resolved in the crystal structure used as the target, it should also be taken into account during the docking calculations. If the crystallographic studies were not able to resolve the sodium ion then no advantage would be obtained if this is manually inserted in the virtual target. The outcomes of the present analysis are useful for researchers exploiting molecular docking-based virtual screening to efficiently identify novel GPCR antagonists.