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. 2017 Oct 23;18(10):2217.
doi: 10.3390/ijms18102217.

Molecular Docking and Screening Studies of New Natural Sortase A Inhibitors

Georgiana Nitulescu  1 , Isabela Madalina Nicorescu  2 , Octavian Tudorel Olaru  3 , Anca Ungurianu  4 , Dragos Paul Mihai  5 , Anca Zanfirescu  6 , George Mihai Nitulescu  7 , Denisa Margina  8
Affiliations

Molecular Docking and Screening Studies of New Natural Sortase A Inhibitors

Georgiana Nitulescu et al. Int J Mol Sci. .

Abstract

To date, multi-drug resistant bacteria represent an increasing health threat, with a high impact on mortality, morbidity, and health costs on a global scale. The ability of bacteria to rapidly and permanently acquire new virulence factors and drug-resistance elements requires the development of new antimicrobial agents and selection of new proper targets, such as sortase A. This specific bacterial target plays an important role in the virulence of many Gram-positive pathogens, and its inhibition should produce a mild evolutionary pressure which will not favor the development of resistance. A primary screening using a fluorescence resonance energy transfer assay was used to experimentally evaluate the inhibitory activity of several compounds on sortase A. Using molecular docking and structure-activity relationship analyses, several lead inhibitors were identified, which were further tested for antimicrobial activity using the well diffusion test and minimum inhibitory concentration. The toxicity was assessed using the Daphnia magna test and used as a future screening filter. Three natural compounds were identified in this study as promising candidates for further development into therapeutically useful anti-infective agents that could be used to treat infections caused by multi-drug resistant bacterial pathogens which include sortase A in their enzymatic set.

Keywords: Daphnia magna; Gram-positive bacteria; MDR-bacteria; Staphylococcus aureus; anti-infective; molecular docking; sortase A.

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Conflict of interest statement

The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

Figures

Figure 1
Figure 1
The inhibitory effect of natural compounds on SrtA after 30, 45, and 60 min. (a) myricetin; (b) palmatine chloride; (c) esculetin.
Figure 2
Figure 2
(A) Docked conformation and interactions of the genistein-SrtA complex; (B) 2D diagram of the predicted interactions; backbone of the protein is colored in grey, β-helices in turquoise, α-helices in red and loops in green. Ligand-protein interactions are colored depending on their type: conventional hydrogen bonds are colored in green, π-σ and π-alkyl interactions are colored in purple and light purple, respectively.
Figure 3
Figure 3
(A) Docked conformation and interactions of the myricetin-SrtA complex; (B) 2D diagram of the predicted interactions; backbone of the protein is colored in grey, β-helices in turquoise, α-helices in red and loops in green. Ligand-protein interactions are colored depending on their type: conventional hydrogen bonds are colored in green, π-σ and π-alkyl interactions are colored in purple and light purple, respectively.
Figure 4
Figure 4
(A) Docked conformation and interactions of the esculetin-SrtA complex; (B) 2D diagram of the predicted interactions; backbone of the protein is colored in grey, β-helices in turquoise, α-helices in red and loops in green. Ligand-protein interactions are colored depending on their type: conventional hydrogen bonds are colored in green, π-σ and π-alkyl interactions are colored in purple and light purple, respectively.
Figure 5
Figure 5
(A) Docked conformation and interactions of the palmatine-SrtA complex; (B) 2D diagram of the predicted interactions; backbone of the protein is colored in grey, β-helices in turquoise, α-helices in red and loops in green. Ligand-protein interactions are colored depending on their type: conventional hydrogen bonds are colored in green, π-σ and π-alkyl interactions are colored in purple and light purple, respectively.
Figure 6
Figure 6
(A) Docked conformation and interactions of the rutin-SrtA complex; (B) 2D diagram of the predicted interactions; backbone of the protein is colored in grey, β-helices in turquoise, α-helices in red and loops in green. Ligand-protein interactions are colored depending on their type: conventional hydrogen bonds are colored in green, π-σ and π-alkyl interactions are colored in purple and light purple, respectively.
Figure 7
Figure 7
(A) Docked conformation and interactions of the troxerutin-SrtA complex; (B) 2D diagram of the predicted interactions; backbone of the protein is colored in grey, β-helices in turquoise, α-helices in red and loops in green. Ligand-protein interactions are colored depending on their type: conventional hydrogen bonds are colored in green, π-σ and π-alkyl interactions are colored in purple and light purple, respectively.
Figure 8
Figure 8
(A) Docked conformation and interactions of the umbelliferone-SrtA complex; (B) 2D diagram of the predicted interactions; backbone of the protein is colored in grey, β-helices in turquoise, α-helices in red and loops in green. Ligand-protein interactions are colored depending on their type: conventional hydrogen bonds are colored in green, π-σ and π-alkyl interactions are colored in purple and light purple, respectively.
Figure 9
Figure 9
Daphnia magna lethality—logarithm of concentration curves at 24 and 48 h for: (a) piperine; (b) chrysin; (c) emodin; (d) podophyllotoxin; (e) umbelliferone; (f) potassium dichromate. Error bars represent standard error of the mean.
Figure 9
Figure 9
Daphnia magna lethality—logarithm of concentration curves at 24 and 48 h for: (a) piperine; (b) chrysin; (c) emodin; (d) podophyllotoxin; (e) umbelliferone; (f) potassium dichromate. Error bars represent standard error of the mean.
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