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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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Related in: MedlinePlus

Two-dimensional structures of Fragment 1 and Fragment 8.Two-dimensional structures of Fragment 1 and 8 are shown in panels A and B, respectively.
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pone-0073344-g003: Two-dimensional structures of Fragment 1 and Fragment 8.Two-dimensional structures of Fragment 1 and 8 are shown in panels A and B, respectively.

Mentions: To identify potential compounds that can be well accommodated in the 150-cavity of NA, we performed in silico screening of a fragment compound library (with 8019 members) onto the modeled structure of 09N1, the latest pandemic influenza virus strain. The Glide score algorithm was used to rank members of the fragment library. Thirty fragments had Glide scores less than -6 kcal/mol, and they were selected as fragment candidates for linking. The small molecules were named based on their score ranks with the prefix “Fragment” (Table 2). With the criteria: LogP range 0-6, molecular weight 300-800 Da, number of hydrogen bond in donor/receptor 2-10 and binding affinity pKd 5-10, four compounds were successfully constructed in the linking stage. The linked molecules were prefixed “Lig”. All of them were generated from Fragment 1 and Fragment 8 (Table 3), and the 2-dimensional structures of Fragment 1 and 8 are shown in Figure 3.


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

Han N, Mu Y - PLoS ONE (2013)

Two-dimensional structures of Fragment 1 and Fragment 8.Two-dimensional structures of Fragment 1 and 8 are shown in panels A and B, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0073344-g003: Two-dimensional structures of Fragment 1 and Fragment 8.Two-dimensional structures of Fragment 1 and 8 are shown in panels A and B, respectively.
Mentions: To identify potential compounds that can be well accommodated in the 150-cavity of NA, we performed in silico screening of a fragment compound library (with 8019 members) onto the modeled structure of 09N1, the latest pandemic influenza virus strain. The Glide score algorithm was used to rank members of the fragment library. Thirty fragments had Glide scores less than -6 kcal/mol, and they were selected as fragment candidates for linking. The small molecules were named based on their score ranks with the prefix “Fragment” (Table 2). With the criteria: LogP range 0-6, molecular weight 300-800 Da, number of hydrogen bond in donor/receptor 2-10 and binding affinity pKd 5-10, four compounds were successfully constructed in the linking stage. The linked molecules were prefixed “Lig”. All of them were generated from Fragment 1 and Fragment 8 (Table 3), and the 2-dimensional structures of Fragment 1 and 8 are shown in Figure 3.

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