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Int. J. Mol. Sci. 2009, 10(9), 3918-3930; doi:10.3390/ijms10093918
Article

A Proline-Based Neuraminidase Inhibitor: DFT Studies on the Zwitterion Conformation, Stability and Formation

1
, 1
, 1
 and 1,2,*
Received: 6 August 2009; Accepted: 2 September 2009 / Published: 7 September 2009
(This article belongs to the Special Issue Applications of Density Functional Theory)
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Abstract: The designs of potent neuraminidase (NA) inhibitors are an efficient way to deal with the recent “2009 H1N1” influenza epidemic. In this work, density functional calculations were employed to study the conformation, stability and formation of the zwitterions of 5-[(1R,2S)-1-(acetylamino)-2-methoxy-2-methylpentyl]-4-[(1Z)-1-propenyl]-(4S,5R)-D-proline (BL), a proline-based NA inhibitor. Compared to proline, the zwitterion stability of BL is enhanced by 1.76 kcal mol-1 due to the introduction of functional groups. However, the zwitterion of BL will not represent a local minimum on the potential energy surface until the number of water molecules increases up to two (n = 2). With the addition of two and three water molecules, the energy differences between the zwitterions and corresponding canonical isomers were calculated at 3.13 and -1.54 kcal mol-1, respectively. The zwitterions of BL are mainly stabilized by the H-bonds with the water molecules, especially in the case of three water molecules where the carboxyl-O atoms are largely coordination-saturated by three H-bonds of medium strengths, causing the zwitterion stability even superior to the canonical isomer. With the presence of two and three water molecules, the energy barriers for the conversion processes from the canonical isomers to the zwitterions are equal to 4.96 and 3.13 kcal mol-1, respectively. It indicated that the zwitterion formation is facile to take place with addition of two molecules and further facilitated by more water molecules. Besides, the zwitterion formation of BL is finished in a single step, different from other NA inhibitors. Owing to the above advantages, BL is a good NA inhibitor candidate and more attention should be paid to explorations of BL-based drugs.
Keywords: density functional calculations; neuraminidase inhibitor; relative stability; water; zwitterions density functional calculations; neuraminidase inhibitor; relative stability; water; zwitterions
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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MDPI and ACS Style

Yang, Z.-W.; Wu, X.-M.; Zhou, L.-J.; Yang, G. A Proline-Based Neuraminidase Inhibitor: DFT Studies on the Zwitterion Conformation, Stability and Formation. Int. J. Mol. Sci. 2009, 10, 3918-3930.

AMA Style

Yang Z-W, Wu X-M, Zhou L-J, Yang G. A Proline-Based Neuraminidase Inhibitor: DFT Studies on the Zwitterion Conformation, Stability and Formation. International Journal of Molecular Sciences. 2009; 10(9):3918-3930.

Chicago/Turabian Style

Yang, Zhi-Wei; Wu, Xiao-Min; Zhou, Li-Jun; Yang, Gang. 2009. "A Proline-Based Neuraminidase Inhibitor: DFT Studies on the Zwitterion Conformation, Stability and Formation." Int. J. Mol. Sci. 10, no. 9: 3918-3930.



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