To predict potential inhibitors of alpha-enolase to reduce plasminogen binding of Streptococcus pneumoniae (S. pneumoniae) that may lead as an orally active drug. S. pneumoniae remains dominant in causing invasive diseases. Fibrinolytic pathway is a critical factor of S. pneumoniae to invade and progression of disease in the host body. Besides the low mass on the cell surface, alpha-enolase possesses significant plasminogen binding among all exposed proteins.
In-silico based drug designing approach was implemented for evaluating potential inhibitors against alpha-enolase based on their binding affinities, energy score and pharmacokinetics. Lipinski’s rule of five (LRo5) and Egan’s (Brain Or IntestinaL EstimateD) BOILED-Egg methods were executed to predict the best ligand for biological systems.
Molecular docking analysis revealed, Sodium (1,5-dihydroxy-2-oxopyrrolidin-3-yl)-hydroxy-dioxidophosphanium (SF-2312) as a promising inhibitor that fabricates finest attractive charges and conventional hydrogen bonds with S. pneumoniae alpha-enolase. Moreover, the pharmacokinetics of SF-2312 predict it as a therapeutic inhibitor for clinical trials. Like SF-2312, phosphono-acetohydroxamate (PhAH) also constructed adequate interactions at the active site of alpha-enolase, but it predicted less favourable than SF-2312 based on binding affinity.
Briefly, SF-2312 and PhAH ligands could inhibit the role of alpha-enolase to restrain plasminogen binding, invasion and progression of S. pneumoniae. As per our investigation and analysis, SF-2312 is the most potent naturally existing inhibitor of S. pneumoniae alpha-enolase in current time.
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((3 s,5 s)-1,5-Dihydroxy-3-Methyl-2-Oxopyrrolidin-3-Yl)phosphonic acid
[(3 s)-1-Hydroxy-2-Oxopiperidin-3-Yl]phosphonic acid
Brain Or IntestinaL EstimateD
(1 s)-1-Fluoro-2-(Hydroxyamino)-2-Oxoethyl]phosphonic acid
Invasive pneumococcal disease
Lipinski’s rule of five
Neutrophil Extracellular Traps
- S. pneumoniae :
Topological polar surface area
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The research is supported by FRGS/1 /2017/SKK06iUNISZA/02/1 under Kementerian Pendidikan Malaysia (KPM) and Universiti Sultan Zainal Abidin.
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Hassan, M., Baig, A.A., Attique, S.A. et al. Molecular docking of alpha-enolase to elucidate the promising candidates against Streptococcus pneumoniae infection. DARU J Pharm Sci (2021). https://doi.org/10.1007/s40199-020-00384-3
- Enolase ligands
- Molecular docking