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Locking the 150-cavity open: in silico design and verification of influenza neuraminidase inhibitors.

Han N, Mu Y - PLoS ONE (2013)

Bottom Line: The resultant new ligands may bind both the active site and the 150-cavity of NA simultaneously.Moreover, two control systems, a positive control using Zanamivir and a negative control using a low-affinity ligand 3-(p-tolyl) allyl-Neu5Ac2en (ETT, abbreviation reported in the PDB) found in a recent experimental work, were employed to calibrate the simulation method.During the simulations, ETT was observed to detach from NA, on the contrary, both Zanamivir and our designed ligand bind NA firmly.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.

ABSTRACT
Neuraminidase (NA) of influenza is a key target for virus infection control and the recently discovered open 150-cavity in group-1 NA provides new opportunity for novel inhibitors design. In this study, we used a combination of theoretical methods including fragment docking, molecular linking and molecular dynamics simulations to design ligands that specifically target at the 150-cavity. Through in silico screening of a fragment compound library on the open 150-cavity of NA, a few best scored fragment compounds were selected to link with Zanamivir, one NA-targeting drug. The resultant new ligands may bind both the active site and the 150-cavity of NA simultaneously. Extensive molecular dynamics simulations in explicit solvent were applied to validate the binding between NA and the designed ligands. Moreover, two control systems, a positive control using Zanamivir and a negative control using a low-affinity ligand 3-(p-tolyl) allyl-Neu5Ac2en (ETT, abbreviation reported in the PDB) found in a recent experimental work, were employed to calibrate the simulation method. During the simulations, ETT was observed to detach from NA, on the contrary, both Zanamivir and our designed ligand bind NA firmly. Our study provides a prospective way to design novel inhibitors for controlling the spread of influenza virus.

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Hydrogen bonds between ligands and active site residues in different systems.The number of hydrogen bonds formed between ligands and active site residues of 09N1. ETT in three repeated trajectories is shown in black, red and blue symbols. ZMR is shown in green color. The number of hydrogen bonds formed between Lig 1 and 09N1 is shown in purple with triangle symbols. Error bars represent standard deviations of the number of hydrogen bonds in four protomers in a single system.
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pone-0073344-g009: Hydrogen bonds between ligands and active site residues in different systems.The number of hydrogen bonds formed between ligands and active site residues of 09N1. ETT in three repeated trajectories is shown in black, red and blue symbols. ZMR is shown in green color. The number of hydrogen bonds formed between Lig 1 and 09N1 is shown in purple with triangle symbols. Error bars represent standard deviations of the number of hydrogen bonds in four protomers in a single system.

Mentions: There are several charged residues in the active site of NA. The ligand interacts with the active site mainly through electrostatic interactions or hydrogen bond interactions. To check the detailed interaction between ligands and the active site, hydrogen bond analysis was performed based on the whole trajectories. Figure 9 shows that ETT cannot form stable interactions with 09N1 in three different trajectories. On the contrary, the hydrogen bonds formed between ZMR/Lig 1 and 09N1 remained stable. Compared to ZMR, Lig 1 formed more hydrogen bonds with E119, G147, D151 and R430. Meanwhile the flexibility of Lig 1 is larger than ZMR in the binding pocket of 09N1. G147 and D151 are in the 150-loop and R430 is in the 430-loop. These residues are the original designed targets for Lig 1. The stable hydrogen bonds between Lig 1 and the 150/430-loop indicate that the originally expected interactions were well maintained during simulations.


Locking the 150-cavity open: in silico design and verification of influenza neuraminidase inhibitors.

Han N, Mu Y - PLoS ONE (2013)

Hydrogen bonds between ligands and active site residues in different systems.The number of hydrogen bonds formed between ligands and active site residues of 09N1. ETT in three repeated trajectories is shown in black, red and blue symbols. ZMR is shown in green color. The number of hydrogen bonds formed between Lig 1 and 09N1 is shown in purple with triangle symbols. Error bars represent standard deviations of the number of hydrogen bonds in four protomers in a single system.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3755005&req=5

pone-0073344-g009: Hydrogen bonds between ligands and active site residues in different systems.The number of hydrogen bonds formed between ligands and active site residues of 09N1. ETT in three repeated trajectories is shown in black, red and blue symbols. ZMR is shown in green color. The number of hydrogen bonds formed between Lig 1 and 09N1 is shown in purple with triangle symbols. Error bars represent standard deviations of the number of hydrogen bonds in four protomers in a single system.
Mentions: There are several charged residues in the active site of NA. The ligand interacts with the active site mainly through electrostatic interactions or hydrogen bond interactions. To check the detailed interaction between ligands and the active site, hydrogen bond analysis was performed based on the whole trajectories. Figure 9 shows that ETT cannot form stable interactions with 09N1 in three different trajectories. On the contrary, the hydrogen bonds formed between ZMR/Lig 1 and 09N1 remained stable. Compared to ZMR, Lig 1 formed more hydrogen bonds with E119, G147, D151 and R430. Meanwhile the flexibility of Lig 1 is larger than ZMR in the binding pocket of 09N1. G147 and D151 are in the 150-loop and R430 is in the 430-loop. These residues are the original designed targets for Lig 1. The stable hydrogen bonds between Lig 1 and the 150/430-loop indicate that the originally expected interactions were well maintained during simulations.

Bottom Line: The resultant new ligands may bind both the active site and the 150-cavity of NA simultaneously.Moreover, two control systems, a positive control using Zanamivir and a negative control using a low-affinity ligand 3-(p-tolyl) allyl-Neu5Ac2en (ETT, abbreviation reported in the PDB) found in a recent experimental work, were employed to calibrate the simulation method.During the simulations, ETT was observed to detach from NA, on the contrary, both Zanamivir and our designed ligand bind NA firmly.

View Article: PubMed Central - PubMed

Affiliation: School of Biological Sciences, Nanyang Technological University, Singapore, Singapore.

ABSTRACT
Neuraminidase (NA) of influenza is a key target for virus infection control and the recently discovered open 150-cavity in group-1 NA provides new opportunity for novel inhibitors design. In this study, we used a combination of theoretical methods including fragment docking, molecular linking and molecular dynamics simulations to design ligands that specifically target at the 150-cavity. Through in silico screening of a fragment compound library on the open 150-cavity of NA, a few best scored fragment compounds were selected to link with Zanamivir, one NA-targeting drug. The resultant new ligands may bind both the active site and the 150-cavity of NA simultaneously. Extensive molecular dynamics simulations in explicit solvent were applied to validate the binding between NA and the designed ligands. Moreover, two control systems, a positive control using Zanamivir and a negative control using a low-affinity ligand 3-(p-tolyl) allyl-Neu5Ac2en (ETT, abbreviation reported in the PDB) found in a recent experimental work, were employed to calibrate the simulation method. During the simulations, ETT was observed to detach from NA, on the contrary, both Zanamivir and our designed ligand bind NA firmly. Our study provides a prospective way to design novel inhibitors for controlling the spread of influenza virus.

Show MeSH
Related in: MedlinePlus