Carbonic anhydrase inhibitors. the X-ray crystal structure of human isoform II in adduct with an adamantyl analogue of acetazolamide resides in a less utilized binding pocket than most hydrophobic inhibitors

Balendu Sankara Avvaru; Jason M. Wagner; Alfonso Maresca; Andrea Scozzafava; Arthur H. Robbins; Claudiu T. Supuran; Robert McKenna

doi:10.1016/j.bmcl.2010.06.082

Carbonic anhydrase inhibitors. the X-ray crystal structure of human isoform II in adduct with an adamantyl analogue of acetazolamide resides in a less utilized binding pocket than most hydrophobic inhibitors

Balendu Sankara Avvaru, Jason M. Wagner, Alfonso Maresca, Andrea Scozzafava, Arthur H. Robbins, Claudiu T. Supuran, Robert McKenna

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

69 Scopus citations

Abstract

We investigated the inhibitory activity of several 1,3,4-thiadiazole- sulfonamides against all catalytically active CA (EC 4.2.1.1), CA I-XV. The tail derivatizing the 5-position in the 1,3,4-thiadiazole-2-sulfonamide scaffold was observed to be critical as an inhibitory determinant of these compounds. The high resolution X-ray crystal structure of hCA II in complex with 5-(1-adamantylcarboxamido)-1,3,4-thiadiazole-2-sulfonamide, showed the adamantyl moiety of the inhibitor residing in a less utilized binding pocket than that of most hydrophobic inhibitors, lined by the amino acid residues Ile91, Val121 and Phe131. This binding site may explain the diverse inhibition profiles of 5-carboxamide- and sufonamide-derivatized 1,3,4-thiadiazole-2-sulfonamides and offers a hot spot for designing isoform selective inhibitors, considering that residues 91 and 131 are highly variable among the 13 catalytically active isoforms.

Original language	English (US)
Pages (from-to)	4376-4381
Number of pages	6
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	20
Issue number	15
DOIs	https://doi.org/10.1016/j.bmcl.2010.06.082
State	Published - Aug 1 2010
Externally published	Yes

Keywords

1,3,4-Thiadiazole-2-sulfonamide
Carbonic anhydrase
Enzyme-inhibitor
Isoforms I-XV
Sulfonamide
X-ray crystallography

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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Avvaru, B. S., Wagner, J. M., Maresca, A., Scozzafava, A., Robbins, A. H., Supuran, C. T., & McKenna, R. (2010). Carbonic anhydrase inhibitors. the X-ray crystal structure of human isoform II in adduct with an adamantyl analogue of acetazolamide resides in a less utilized binding pocket than most hydrophobic inhibitors. Bioorganic and Medicinal Chemistry Letters, 20(15), 4376-4381. https://doi.org/10.1016/j.bmcl.2010.06.082

Carbonic anhydrase inhibitors. the X-ray crystal structure of human isoform II in adduct with an adamantyl analogue of acetazolamide resides in a less utilized binding pocket than most hydrophobic inhibitors. / Avvaru, Balendu Sankara; Wagner, Jason M.; Maresca, Alfonso et al.
In: Bioorganic and Medicinal Chemistry Letters, Vol. 20, No. 15, 01.08.2010, p. 4376-4381.

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

Avvaru, BS, Wagner, JM, Maresca, A, Scozzafava, A, Robbins, AH, Supuran, CT & McKenna, R 2010, 'Carbonic anhydrase inhibitors. the X-ray crystal structure of human isoform II in adduct with an adamantyl analogue of acetazolamide resides in a less utilized binding pocket than most hydrophobic inhibitors', Bioorganic and Medicinal Chemistry Letters, vol. 20, no. 15, pp. 4376-4381. https://doi.org/10.1016/j.bmcl.2010.06.082

Avvaru BS, Wagner JM, Maresca A, Scozzafava A, Robbins AH, Supuran CT et al. Carbonic anhydrase inhibitors. the X-ray crystal structure of human isoform II in adduct with an adamantyl analogue of acetazolamide resides in a less utilized binding pocket than most hydrophobic inhibitors. Bioorganic and Medicinal Chemistry Letters. 2010 Aug 1;20(15):4376-4381. doi: 10.1016/j.bmcl.2010.06.082

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title = "Carbonic anhydrase inhibitors. the X-ray crystal structure of human isoform II in adduct with an adamantyl analogue of acetazolamide resides in a less utilized binding pocket than most hydrophobic inhibitors",

abstract = "We investigated the inhibitory activity of several 1,3,4-thiadiazole- sulfonamides against all catalytically active CA (EC 4.2.1.1), CA I-XV. The tail derivatizing the 5-position in the 1,3,4-thiadiazole-2-sulfonamide scaffold was observed to be critical as an inhibitory determinant of these compounds. The high resolution X-ray crystal structure of hCA II in complex with 5-(1-adamantylcarboxamido)-1,3,4-thiadiazole-2-sulfonamide, showed the adamantyl moiety of the inhibitor residing in a less utilized binding pocket than that of most hydrophobic inhibitors, lined by the amino acid residues Ile91, Val121 and Phe131. This binding site may explain the diverse inhibition profiles of 5-carboxamide- and sufonamide-derivatized 1,3,4-thiadiazole-2-sulfonamides and offers a hot spot for designing isoform selective inhibitors, considering that residues 91 and 131 are highly variable among the 13 catalytically active isoforms.",

keywords = "1,3,4-Thiadiazole-2-sulfonamide, Carbonic anhydrase, Enzyme-inhibitor, Isoforms I-XV, Sulfonamide, X-ray crystallography",

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note = "Funding Information: This research was financed in part by a grant of the 6th Framework Programme of the European Union (DeZnIT project) and by a 7th FP EU project (METOXIA) to A.S. and C.T.S., in part by the NIH GM2515 and NIH GM25154 grants and by a Thomas Maren grant to R.M. R.M. would also like to thank the Center of Structural Biology for support of the X-ray facility at UF.",

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AU - Avvaru, Balendu Sankara

AU - Wagner, Jason M.

AU - Maresca, Alfonso

AU - Scozzafava, Andrea

AU - Robbins, Arthur H.

AU - Supuran, Claudiu T.

AU - McKenna, Robert

N1 - Funding Information: This research was financed in part by a grant of the 6th Framework Programme of the European Union (DeZnIT project) and by a 7th FP EU project (METOXIA) to A.S. and C.T.S., in part by the NIH GM2515 and NIH GM25154 grants and by a Thomas Maren grant to R.M. R.M. would also like to thank the Center of Structural Biology for support of the X-ray facility at UF.

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N2 - We investigated the inhibitory activity of several 1,3,4-thiadiazole- sulfonamides against all catalytically active CA (EC 4.2.1.1), CA I-XV. The tail derivatizing the 5-position in the 1,3,4-thiadiazole-2-sulfonamide scaffold was observed to be critical as an inhibitory determinant of these compounds. The high resolution X-ray crystal structure of hCA II in complex with 5-(1-adamantylcarboxamido)-1,3,4-thiadiazole-2-sulfonamide, showed the adamantyl moiety of the inhibitor residing in a less utilized binding pocket than that of most hydrophobic inhibitors, lined by the amino acid residues Ile91, Val121 and Phe131. This binding site may explain the diverse inhibition profiles of 5-carboxamide- and sufonamide-derivatized 1,3,4-thiadiazole-2-sulfonamides and offers a hot spot for designing isoform selective inhibitors, considering that residues 91 and 131 are highly variable among the 13 catalytically active isoforms.

AB - We investigated the inhibitory activity of several 1,3,4-thiadiazole- sulfonamides against all catalytically active CA (EC 4.2.1.1), CA I-XV. The tail derivatizing the 5-position in the 1,3,4-thiadiazole-2-sulfonamide scaffold was observed to be critical as an inhibitory determinant of these compounds. The high resolution X-ray crystal structure of hCA II in complex with 5-(1-adamantylcarboxamido)-1,3,4-thiadiazole-2-sulfonamide, showed the adamantyl moiety of the inhibitor residing in a less utilized binding pocket than that of most hydrophobic inhibitors, lined by the amino acid residues Ile91, Val121 and Phe131. This binding site may explain the diverse inhibition profiles of 5-carboxamide- and sufonamide-derivatized 1,3,4-thiadiazole-2-sulfonamides and offers a hot spot for designing isoform selective inhibitors, considering that residues 91 and 131 are highly variable among the 13 catalytically active isoforms.

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KW - Isoforms I-XV

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Carbonic anhydrase inhibitors. the X-ray crystal structure of human isoform II in adduct with an adamantyl analogue of acetazolamide resides in a less utilized binding pocket than most hydrophobic inhibitors

Abstract

Keywords

ASJC Scopus subject areas

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