Influenza neuraminidase inhibitors: Structure-based design of a novel inhibitor series

Vincent Stoll; Kent D. Stewart; Clarence J. Maring; Steven Muchmore; Vincent Giranda; Yu gui Y. Gu; Gary Wang; Yuanwei Chen; Minghua Sun; Chen Zhao; April L. Kennedy; Darold L. Madigan; Yibo Xu; Ayda Saldivar; Warren Kati; Graeme Laver; Thomas Sowin; Hing L. Sham; Jonathan Greer; Dale Kempf

doi:10.1021/bi0205449

Influenza neuraminidase inhibitors: Structure-based design of a novel inhibitor series

Vincent Stoll^*, Kent D. Stewart, Clarence J. Maring, Steven Muchmore, Vincent Giranda, Yu gui Y. Gu, Gary Wang, Yuanwei Chen, Minghua Sun, Chen Zhao, April L. Kennedy, Darold L. Madigan, Yibo Xu, Ayda Saldivar, Warren Kati, Graeme Laver, Thomas Sowin, Hing L. Sham, Jonathan Greer, Dale Kempf

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

134 Citations (Scopus)

Abstract

Combinatorial and structure-based medicinal chemistry strategies were used together to advance a lead compound with an activity of K_i = 58 μM via a potency enhancement of < 70 000-fold to an analogue with an activity of K_i = 0.8 nM against influenza neuraminidase (A/Tokyo/67). Lead optimization was initiated using molecular modeling and combinatorial chemistry. Protein crystal structures revealed that inconsistent structure - activity relationship (SAR) data resulted from different binding orientations of the inhibitor core five-membered rings from one series to another. Binding modes for a series of compounds showed up to a 180° variation in orientation of the five-membered ring within the active site. Potent analogues were only achieved with chemical series that were observed to bind in the same orientation and yielded consistent SAR. In one series, consistent binding was obtained by an unprecedented occupation of a negatively charged binding pocket by a neutral methyl ester unit. The structural rationale for this novel SAR variation, based on protein crystallographic data, is given.

Original language	English
Pages (from-to)	718-727
Number of pages	10
Journal	Biochemistry
Volume	42
Issue number	3
DOIs	https://doi.org/10.1021/bi0205449
Publication status	Published - 28 Jan 2003

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Stoll, V., Stewart, K. D., Maring, C. J., Muchmore, S., Giranda, V., Gu, Y. G. Y., Wang, G., Chen, Y., Sun, M., Zhao, C., Kennedy, A. L., Madigan, D. L., Xu, Y., Saldivar, A., Kati, W., Laver, G., Sowin, T., Sham, H. L., Greer, J., & Kempf, D. (2003). Influenza neuraminidase inhibitors: Structure-based design of a novel inhibitor series. Biochemistry, 42(3), 718-727. https://doi.org/10.1021/bi0205449

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title = "Influenza neuraminidase inhibitors: Structure-based design of a novel inhibitor series",

abstract = "Combinatorial and structure-based medicinal chemistry strategies were used together to advance a lead compound with an activity of Ki = 58 μM via a potency enhancement of < 70 000-fold to an analogue with an activity of Ki = 0.8 nM against influenza neuraminidase (A/Tokyo/67). Lead optimization was initiated using molecular modeling and combinatorial chemistry. Protein crystal structures revealed that inconsistent structure - activity relationship (SAR) data resulted from different binding orientations of the inhibitor core five-membered rings from one series to another. Binding modes for a series of compounds showed up to a 180° variation in orientation of the five-membered ring within the active site. Potent analogues were only achieved with chemical series that were observed to bind in the same orientation and yielded consistent SAR. In one series, consistent binding was obtained by an unprecedented occupation of a negatively charged binding pocket by a neutral methyl ester unit. The structural rationale for this novel SAR variation, based on protein crystallographic data, is given.",

author = "Vincent Stoll and Stewart, {Kent D.} and Maring, {Clarence J.} and Steven Muchmore and Vincent Giranda and Gu, {Yu gui Y.} and Gary Wang and Yuanwei Chen and Minghua Sun and Chen Zhao and Kennedy, {April L.} and Madigan, {Darold L.} and Yibo Xu and Ayda Saldivar and Warren Kati and Graeme Laver and Thomas Sowin and Sham, {Hing L.} and Jonathan Greer and Dale Kempf",

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Stoll, V, Stewart, KD, Maring, CJ, Muchmore, S, Giranda, V, Gu, YGY, Wang, G, Chen, Y, Sun, M, Zhao, C, Kennedy, AL, Madigan, DL, Xu, Y, Saldivar, A, Kati, W, Laver, G, Sowin, T, Sham, HL, Greer, J & Kempf, D 2003, 'Influenza neuraminidase inhibitors: Structure-based design of a novel inhibitor series', Biochemistry, vol. 42, no. 3, pp. 718-727. https://doi.org/10.1021/bi0205449

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AU - Stoll, Vincent

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AU - Maring, Clarence J.

AU - Muchmore, Steven

AU - Giranda, Vincent

AU - Gu, Yu gui Y.

AU - Wang, Gary

AU - Chen, Yuanwei

AU - Sun, Minghua

AU - Zhao, Chen

AU - Kennedy, April L.

AU - Madigan, Darold L.

AU - Xu, Yibo

AU - Saldivar, Ayda

AU - Kati, Warren

AU - Laver, Graeme

AU - Sowin, Thomas

AU - Sham, Hing L.

AU - Greer, Jonathan

AU - Kempf, Dale

PY - 2003/1/28

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AB - Combinatorial and structure-based medicinal chemistry strategies were used together to advance a lead compound with an activity of Ki = 58 μM via a potency enhancement of < 70 000-fold to an analogue with an activity of Ki = 0.8 nM against influenza neuraminidase (A/Tokyo/67). Lead optimization was initiated using molecular modeling and combinatorial chemistry. Protein crystal structures revealed that inconsistent structure - activity relationship (SAR) data resulted from different binding orientations of the inhibitor core five-membered rings from one series to another. Binding modes for a series of compounds showed up to a 180° variation in orientation of the five-membered ring within the active site. Potent analogues were only achieved with chemical series that were observed to bind in the same orientation and yielded consistent SAR. In one series, consistent binding was obtained by an unprecedented occupation of a negatively charged binding pocket by a neutral methyl ester unit. The structural rationale for this novel SAR variation, based on protein crystallographic data, is given.

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Influenza neuraminidase inhibitors: Structure-based design of a novel inhibitor series

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