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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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Chemical structures of NA inhibitors and derivatives.Panels A, B and C show the chemical structure of Neu5Ac2en, ZMR and ETT, respectively.
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pone-0073344-g002: Chemical structures of NA inhibitors and derivatives.Panels A, B and C show the chemical structure of Neu5Ac2en, ZMR and ETT, respectively.

Mentions: After docking, 30 fragment molecules were found to have glide scores of less than -6 kcal/mol. These fragments were chosen as the fragment candidates to be linked with the scaffold, ZMR drug molecule. The linked molecules were further filtered with a series of criteria: LogP (0-6), molecular weight (300-800 da), number of hydrogen bond donors/receptors (2–10), and binding affinity pKd (5–10). LigBuilder v 1.2 was applied to construct novel inhibitors [33]. In the linking stage, ZMR was used as the linking scaffold onto which the selected fragment candidates were added. The C-3 position on ZMR is the only position that can accommodate growth towards the 150-cavity with minimal distortion of other NA contact sites (Figure 2). In total, 19755 compounds were generated from the linking process, but the majority was filtered using the above criteria. Finally, four ligands were successfully linked. Explicit water MD simulations were performed on NA-ligands complex to verify the stability of the binding modes.


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

Han N, Mu Y - PLoS ONE (2013)

Chemical structures of NA inhibitors and derivatives.Panels A, B and C show the chemical structure of Neu5Ac2en, ZMR and ETT, respectively.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0073344-g002: Chemical structures of NA inhibitors and derivatives.Panels A, B and C show the chemical structure of Neu5Ac2en, ZMR and ETT, respectively.
Mentions: After docking, 30 fragment molecules were found to have glide scores of less than -6 kcal/mol. These fragments were chosen as the fragment candidates to be linked with the scaffold, ZMR drug molecule. The linked molecules were further filtered with a series of criteria: LogP (0-6), molecular weight (300-800 da), number of hydrogen bond donors/receptors (2–10), and binding affinity pKd (5–10). LigBuilder v 1.2 was applied to construct novel inhibitors [33]. In the linking stage, ZMR was used as the linking scaffold onto which the selected fragment candidates were added. The C-3 position on ZMR is the only position that can accommodate growth towards the 150-cavity with minimal distortion of other NA contact sites (Figure 2). In total, 19755 compounds were generated from the linking process, but the majority was filtered using the above criteria. Finally, four ligands were successfully linked. Explicit water MD simulations were performed on NA-ligands complex to verify the stability of the binding modes.

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