Ginger (Zingiber officinale) phytochemicals-gingerenone-A and shogaol inhibit SaHPPK: molecular docking, molecular dynamics simulations and in vitro approaches

Abstract

Background: Antibiotic resistance is a defense mechanism, harbored by pathogens to survive under unfavorable conditions. Among several antibiotic resistant microbial consortium, Staphylococcus aureus is one of the most havoc microorganisms. Staphylococcus aureus encodes a unique enzyme 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase (SaHPPK), against which, none of existing antibiotics have been reported.

Methods: Computational approaches have been instrumental in designing and discovering new drugs for several diseases. The present study highlights the impact of ginger phytochemicals on Staphylococcus aureus SaHPPK. Herein, we have retrieved eight ginger phytochemicals from published literature and investigated their inhibitory interactions with SaHPPK. To authenticate our work, the investigation proceeds considering the known antibiotics alongside the phytochemicals. Molecular docking was performed employing GOLD and CDOCKER. The compounds with the highest dock score from both the docking programmes were tested for their inhibitory capability in vitro. The binding conformations that were seated within the binding pocket showing strong interactions with the active sites residues rendered by highest dock score were forwarded towards the molecular dynamic (MD) simulation analysis.

Results: Based on molecular dock scores, molecular interaction with catalytic active residues and MD simulations studies, two ginger phytochemicals, gingerenone-A and shogaol have been proposed as candidate inhibitors against Staphylococcus aureus. They have demonstrated higher dock scores than the known antibiotics and have represented interactions with the key residues within the active site. Furthermore, these compounds have rendered considerable inhibitory activity when tested in vitro. Additionally, their superiority was corroborated by stable MD results conducted for 100 ns employing GROMACS package.

Conclusions: Finally, we suggest that gingerenone-A and shogaol may either be potential SaHPPK inhibitors or can be used as fundamental platforms for novel SaHPPK inhibitor development.

Keywords: 6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase; GOLD; Ginger phytochemicals; Gingerenone-A; MD simulations; Shogaol.

Fig. 1

2D structures of the selected phytochemicals

Fig. 2

Antimicrobial activity of shogaol, gingerenone-A and amoxicillin expressed by zone of inhibition in mm

Fig. 3

RMSD profiles of ten systems during 100 ns. The plots show variations during initial simulations and are stable towards last 20 ns. a Reference, b amoxicillin, c gingerenone-A, d gingerol, e shogaol, f zingerone, g 6dehydrogingerdion, h paradol, i trans-1,8-cineole-3,6-dihydroxy-3-O-β-d-glucopyranoside, j trans-3-hydroxy-1,8-cineole-O-β-d-glucopyranoside

Fig. 4

Potential energy plots of ten systems during 100 ns. The plots appear to be well converged between − 390,000 and − 395,000 kJ/mol. a Reference, b amoxicillin, c gingerenone-A, d gingerol, e shogaol, f zingerone, g 6dehydrogingerdion, h paradol, i trans-1,8-cineole-3,6-dihydroxy-3-O-β-d-glucopyranoside, j trans-3-hydroxy-1,8-cineole-O-β-d-glucopyranoside

Fig. 5

RMSF plots during 100 ns. Blue box denotes the variations notices in the profiles. The RMSF profile of amoxicillin is found to be relatively deviated. a The RMSF of the residues. b The RMSF of the corresponding fluctuating atoms

Fig. 6

Binding pattern of the co-crystal and the ginger phytochemicals. Only polar carbons are shown for clarity. Figure on the left depicts the superimposition of the ligands and figure right is its enlarged structure. The protein is represented in steel and the ligands in stick. The water molecule is denoted in blue and the Mg²⁺ ions in green

Fig. 7

Molecular interactions and the binding mode conformation of the reference and the phytochemicals with the protein target. Green dashed lines demonstrate the hydrogen bonds between the protein and the ligands. The blue dashed lines represent the binding of the water molecule and Asp95. The protein is represented in orange stick. The water molecule is denoted in blue and the Mg²⁺ ions in green. a Reference, b amoxicillin, c gingerenone-A, d gingerol, e shogaol, f zingerone, g 6dehydrogingerdion, h paradol, i trans-1,8-cineole-3,6-dihydroxy-3-O-β-d-glucopyranoside, j trans-3-hydroxy-1,8-cineole-O-β-d-glucopyranoside

Fig. 8

Different conformations exhibited by loop 1 (residues 1–9, in brown loop 2 (residues 43–53, denoted in olive green) and loop 3 (residues 82–92, represented in bottle green). Loop 1 and loop 2 remained semi-closed and closed in all the complexes, while the conformational changes were noticed with loop 3. The protein is represented in steel and the ligands in stick. The water molecule is denoted in blue and the Mg²⁺ ions in green