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. 2022 Oct 11;27(20):6777.
doi: 10.3390/molecules27206777.

Hierarchical Virtual Screening and Binding Free Energy Prediction of Potential Modulators of Aedes Aegypti Odorant-Binding Protein 1

Moysés F A Neto  1 , Joaquín M Campos  2   3 , Amanda P M Cerqueira  1 , Lucio R de Lima  4 , Glauber V Da Costa  4 , Ryan Da S Ramos  4 , Jairo T Magalhães Junior  5 , Cleydson B R Santos  4 , Franco H A Leite  1
Affiliations

Hierarchical Virtual Screening and Binding Free Energy Prediction of Potential Modulators of Aedes Aegypti Odorant-Binding Protein 1

Moysés F A Neto et al. Molecules. .

Abstract

The Aedes aegypti mosquito is the main hematophagous vector responsible for arbovirus transmission in Brazil. The disruption of A. aegypti hematophagy remains one of the most efficient and least toxic methods against these diseases and, therefore, efforts in the research of new chemical entities with repellent activity have advanced due to the elucidation of the functionality of the olfactory receptors and the behavior of mosquitoes. With the growing interest of the pharmaceutical and cosmetic industries in the development of chemical entities with repellent activity, computational studies (e.g., virtual screening and molecular modeling) are a way to prioritize potential modulators with stereoelectronic characteristics (e.g., pharmacophore models) and binding affinity to the AaegOBP1 binding site (e.g., molecular docking) at a lower computational cost. Thus, pharmacophore- and docking-based virtual screening was employed to prioritize compounds from Sigma-Aldrich® (n = 126,851) and biogenic databases (n = 8766). In addition, molecular dynamics (MD) was performed to prioritize the most potential potent compounds compared to DEET according to free binding energy calculations. Two compounds showed adequate stereoelectronic requirements (QFIT > 81.53), AaegOBP1 binding site score (Score > 42.0), volatility and non-toxic properties and better binding free energy value (∆G < −24.13 kcal/mol) compared to DEET ((N,N-diethyl-meta-toluamide)) (∆G = −24.13 kcal/mol).

Keywords: Aedes aegypti; molecular dynamics; odorant binding protein 1; pharmacophore model; virtual screening.

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Conflict of interest statement

The authors declare no conflict of interest and part of methodology of this article has been previously published in Journal of Biomolecular Structure and Dynamics 2020, 40(1); https://doi.org/10.1080/07391102.2020.1808074.

Figures

Figure 1
Figure 1
Pharmacophore-based virtual screening steps.
Figure 2
Figure 2
Docking-based virtual screening step.
Figure 3
Figure 3
(A) Interaction map of ZINC141 in the Poseview software generated by the AaegOBP1 binding site (ChemPLP = 38.88). (B) ZINC141 superimposed on the AaegOBP1 pharmacophore model (QFIT = 85.00). Cyan spheres represent hydrophobic centers (HY) and green spheres represent hydrogen bond donors (HBD). The size of the spheres varies according to the radius tolerance calculated by GALAHAD™. All distances were measured in angstroms. (Legend: Ligand: Carbons are represented in green, nitrogen in blue and oxygen in red).
Figure 4
Figure 4
(A) Interaction map of ZINC047 in the PoseView software generated by the AaegOBP1 binding site (ChemPLP = 54.71). (B) ZINC047 superimposed on the AaegOBP1 pharmacophore model (QFIT = 85.00). Cyan spheres represent hydrophobic centers (HY) and green spheres represent hydrogen bond donors (HBD). The size of the spheres varies according to the radius tolerance calculated by GALAHAD™. All distances were measured in angstroms. (Legend: Ligand: Carbons are represented in green, nitrogen in blue and oxygen in red).
Figure 5
Figure 5
(A) Interaction map of ZINC878 in the PoseView software generated by the AaegOBP1 binding site (ChemPLP = 56.59). (B) ZINC878 superimposed on the model pharmacophore AaegOBP1 (QFIT = 83.86). Cyan spheres represent hydrophobic centers (HY) and green spheres represent hydrogen bond donors (HBD). The size of the spheres varies according to the radius tolerance calculated by GALAHAD™. All distances were measured in angstroms. (Legend: Ligand: Carbons are represented in green, nitrogen in blue and oxygen in red).
Figure 6
Figure 6
(A) Interaction map of ZINC698 in the Poseview software generated by the AaegOBP1 binding site (ChemPLP = 59.81). (B) ZINC698 superimposed on the model pharmacophore AaegOBP1 (QFIT = 83.45). Cyan spheres represent hydrophobic centers (HY) and green spheres represent hydrogen bond donors (HBD). The size of the spheres varies according to the radius tolerance calculated by GALAHAD™. All distances were measured in angstroms. (Legend: Ligand: Carbons are represented in green, nitrogen in blue and oxygen in red).
Figure 7
Figure 7
(A) Interaction map of ZINC305 in the PoseView software generated by the AaegOBP1 binding site (ChemPLP = 42.71). (B) ZINC305 superimposed on the model pharmacophore AaegOBP1 (QFIT = 85.41). Cyan spheres represent hydrophobic centers (HY) and green spheres represent hydrogen bond donors (HBD). The size of the spheres varies according to the radius tolerance calculated by GALAHAD™. All distances were measured in angstroms. (Legend: Ligand: Carbons are represented in green, nitrogen in blue and oxygen in red).
Figure 8
Figure 8
Crystallographic ligand interaction map in the PoseView software generated at the AaegOBP1 binding site. (Legend: Ligand: Carbons are represented in green, nitrogen in blue and oxygen in red).
Figure 9
Figure 9
RMSD plot of Ca atoms in AaegOBP1 APO (black lines) and DEET/AaegOBP1 (red lines), ZINC878/AaegOBP1 (green lines), ZINC141/AaegOBP1 (yellow lines) and ZINC305/AaegOBP1 (blue lines) complexes generated by the xmgrace program.
Figure 10
Figure 10
RMSF plot of the backbone in AaegOBP1 APO (black lines) and DEET/AaegOBP1 (red lines), ZINC878/AaegOBP1 (green lines), ZINC141/AaegOBP1 (yellow lines) and ZINC305/AaegOBP1 (blue lines) complexes generated by the xmgrace program.
Figure 11
Figure 11
Interaction map of representative structures in MD of DEET (A), ZINC878 (B), ZINC305 (C) and ZINC141 (D) at the AaegOBP1 binding site generated by the Poseview server.
See this image and copyright information in PMC

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