HSV-1 Glycoprotein D and Its Surface Receptors: Evaluation of Protein-Protein Interaction and Targeting by Triazole-Based Compounds through In Silico Approaches

Abstract

Protein-protein interactions (PPI) represent attractive targets for drug design. Thus, aiming at a deeper insight into the HSV-1 envelope glycoprotein D (gD), protein-protein docking and dynamic simulations of gD-HVEM and gD-Nectin-1 complexes were performed. The most stable complexes and the pivotal key residues useful for gD to anchor human receptors were identified and used as starting points for a structure-based virtual screening on a library of both synthetic and designed 1,2,3-triazole-based compounds. Their binding properties versus gD interface with HVEM and Nectin-1 along with their structure-activity relationships (SARs) were evaluated. Four [1,2,3]triazolo[4,5-b]pyridines were identified as potential HSV-1 gD inhibitors, for their good theoretical affinity towards all conformations of HSV-1 gD. Overall, this study suggests promising basis for the design of new antiviral agents targeting gD as a valuable strategy to prevent viral attachment and penetration into the host cell.

Keywords: 1,2,3-triazoles; HSV-1; docking; glycoprotein D; molecular dynamics simulations; protein–protein interaction.

Figure 1

Graphical workflow of the applied in silico approaches on HSV-1 gD Pockets.

Figure 2

Surface representation of (A) gD-HVEM and (B) gD-Nectin-1 complexes and focus on the interface with key interactions labelled and displayed in carbon sticks.

Figure 3

Plots of the distances between the residues of gD involved in the interaction at the interface with HVEM after 100 ns of MDs.

Figure 4

Plots of the distances between the residues of gD involved in the interaction at the interface with Nectin-1 after 100 ns of MDs.

Figure 5

Plot of MM/GBSA trend for HVEM and Nectin-1 in complex to gD during 100 ns of MDs.

Figure 6

3D representation of (A) 14, (B) 16, (C) 83, and (D) 85 in complex to the most populated cluster of gD-Pocket 1. gD-Pocket 1 is illustrated in gray, with the residues involved in pivotal contacts shown as carbon sticks. 14, 16, 83, and 85 are depicted as pink, green, violet, and cyan carbon sticks, and H-bonds are indicated as yellow dashed lines.

Figure 7

3D representation of (A) 14, (B) 16, (C) 83, and (D) 85 in complex to the most populated cluster of gD-Pocket 2. gD-Pocket 2 is illustrated in salmon, with the residues involved in pivotal contacts shown as carbon sticks. Compounds 14, 16, 83, and 85 are depicted as pink, green, violet, and cyan carbon sticks, whereas H-bonds and π-π interactions are indicated as yellow and cyan dashed lines, respectively.

Figure 8

RMSD plots of 14, 16, 83, and 85 compounds in complex with (A) gD-Pocket 1 and (B) gD-Pocket 2, calculated on protein’s backbone atoms during 500 ns of MDs.