Using fragment cocktail crystallography to assist inhibitor design of Trypanosoma brucei nucleoside 2-deoxyribosyltransferase

Jürgen Bosch; Mark A. Robien; Christopher Mehlin; Erica Boni; Aaron Riechers; Frederick S. Buckner; Wesley C. Van Voorhis; Peter J. Myler; Elizabeth A. Worthey; George DeTitta; Joseph R. Luft; Angela Lauricella; Stacey Gulde; Lori A. Anderson; Oleksandr Kalyuzhniy; Helen M. Neely; Jenni Ross; Thomas N. Earnest; Michael Soltis; Lori Schoenfeld; Frank Zucker; Ethan A. Merritt; Erkang Fan; Christophe L M J Verlinde; Wim G J Hol

doi:10.1021/jm060429m

Using fragment cocktail crystallography to assist inhibitor design of Trypanosoma brucei nucleoside 2-deoxyribosyltransferase

Jürgen Bosch, Mark A. Robien, Christopher Mehlin, Erica Boni, Aaron Riechers, Frederick S. Buckner, Wesley C. Van Voorhis, Peter J. Myler, Elizabeth A. Worthey, George DeTitta, Joseph R. Luft, Angela Lauricella, Stacey Gulde, Lori A. Anderson, Oleksandr Kalyuzhniy, Helen M. Neely, Jenni Ross, Thomas N. Earnest, Michael Soltis, Lori SchoenfeldFrank Zucker, Ethan A. Merritt, Erkang Fan, Christophe L M J Verlinde, Wim G J Hol

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

52 Scopus citations

Abstract

The 1.8 Å resolution de novo structure of nucleoside 2-deoxyribosyltransferase (EC 2.4.2.6) from Trypanosoma brucei (TbNDRT) has been determined by SAD phasing in an unliganded state and several ligand-bound states. This enzyme is important in the salvage pathway of nucleoside recycling. To identify novel lead compounds, we exploited "fragment cocktail soaks". Out of 304 compounds tried in 31 cocktails, four compounds could be identified crystallographically in the active site. In addition, we demonstrated that very short soaks of ∼10 s are sufficient even for rather hydrophobic ligands to bind in the active site groove, which is promising for the application of similar soaking experiments to less robust crystals of other proteins.

Original language	English (US)
Pages (from-to)	5939-5946
Number of pages	8
Journal	Journal of Medicinal Chemistry
Volume	49
Issue number	20
DOIs	https://doi.org/10.1021/jm060429m
State	Published - Oct 5 2006
Externally published	Yes

ASJC Scopus subject areas

Organic Chemistry

Access to Document

10.1021/jm060429m

Cite this

Bosch, J., Robien, M. A., Mehlin, C., Boni, E., Riechers, A., Buckner, F. S., Van Voorhis, W. C., Myler, P. J., Worthey, E. A., DeTitta, G., Luft, J. R., Lauricella, A., Gulde, S., Anderson, L. A., Kalyuzhniy, O., Neely, H. M., Ross, J., Earnest, T. N., Soltis, M., ... Hol, W. G. J. (2006). Using fragment cocktail crystallography to assist inhibitor design of Trypanosoma brucei nucleoside 2-deoxyribosyltransferase. Journal of Medicinal Chemistry, 49(20), 5939-5946. https://doi.org/10.1021/jm060429m

Bosch, J, Robien, MA, Mehlin, C, Boni, E, Riechers, A, Buckner, FS, Van Voorhis, WC, Myler, PJ, Worthey, EA, DeTitta, G, Luft, JR, Lauricella, A, Gulde, S, Anderson, LA, Kalyuzhniy, O, Neely, HM, Ross, J, Earnest, TN, Soltis, M, Schoenfeld, L, Zucker, F, Merritt, EA, Fan, E, Verlinde, CLMJ & Hol, WGJ 2006, 'Using fragment cocktail crystallography to assist inhibitor design of Trypanosoma brucei nucleoside 2-deoxyribosyltransferase', Journal of Medicinal Chemistry, vol. 49, no. 20, pp. 5939-5946. https://doi.org/10.1021/jm060429m

@article{fad4ecb76d75451e956dd424de573008,

title = "Using fragment cocktail crystallography to assist inhibitor design of Trypanosoma brucei nucleoside 2-deoxyribosyltransferase",

abstract = "The 1.8 {\AA} resolution de novo structure of nucleoside 2-deoxyribosyltransferase (EC 2.4.2.6) from Trypanosoma brucei (TbNDRT) has been determined by SAD phasing in an unliganded state and several ligand-bound states. This enzyme is important in the salvage pathway of nucleoside recycling. To identify novel lead compounds, we exploited {"}fragment cocktail soaks{"}. Out of 304 compounds tried in 31 cocktails, four compounds could be identified crystallographically in the active site. In addition, we demonstrated that very short soaks of ∼10 s are sufficient even for rather hydrophobic ligands to bind in the active site groove, which is promising for the application of similar soaking experiments to less robust crystals of other proteins.",

author = "J{\"u}rgen Bosch and Robien, {Mark A.} and Christopher Mehlin and Erica Boni and Aaron Riechers and Buckner, {Frederick S.} and {Van Voorhis}, {Wesley C.} and Myler, {Peter J.} and Worthey, {Elizabeth A.} and George DeTitta and Luft, {Joseph R.} and Angela Lauricella and Stacey Gulde and Anderson, {Lori A.} and Oleksandr Kalyuzhniy and Neely, {Helen M.} and Jenni Ross and Earnest, {Thomas N.} and Michael Soltis and Lori Schoenfeld and Frank Zucker and Merritt, {Ethan A.} and Erkang Fan and Verlinde, {Christophe L M J} and Hol, {Wim G J}",

year = "2006",

month = oct,

day = "5",

doi = "10.1021/jm060429m",

language = "English (US)",

volume = "49",

pages = "5939--5946",

journal = "Journal of Medicinal Chemistry",

issn = "0022-2623",

publisher = "American Chemical Society",

number = "20",

}

TY - JOUR

T1 - Using fragment cocktail crystallography to assist inhibitor design of Trypanosoma brucei nucleoside 2-deoxyribosyltransferase

AU - Bosch, Jürgen

AU - Robien, Mark A.

AU - Mehlin, Christopher

AU - Boni, Erica

AU - Riechers, Aaron

AU - Buckner, Frederick S.

AU - Van Voorhis, Wesley C.

AU - Myler, Peter J.

AU - Worthey, Elizabeth A.

AU - DeTitta, George

AU - Luft, Joseph R.

AU - Lauricella, Angela

AU - Gulde, Stacey

AU - Anderson, Lori A.

AU - Kalyuzhniy, Oleksandr

AU - Neely, Helen M.

AU - Ross, Jenni

AU - Earnest, Thomas N.

AU - Soltis, Michael

AU - Schoenfeld, Lori

AU - Zucker, Frank

AU - Merritt, Ethan A.

AU - Fan, Erkang

AU - Verlinde, Christophe L M J

AU - Hol, Wim G J

PY - 2006/10/5

Y1 - 2006/10/5

N2 - The 1.8 Å resolution de novo structure of nucleoside 2-deoxyribosyltransferase (EC 2.4.2.6) from Trypanosoma brucei (TbNDRT) has been determined by SAD phasing in an unliganded state and several ligand-bound states. This enzyme is important in the salvage pathway of nucleoside recycling. To identify novel lead compounds, we exploited "fragment cocktail soaks". Out of 304 compounds tried in 31 cocktails, four compounds could be identified crystallographically in the active site. In addition, we demonstrated that very short soaks of ∼10 s are sufficient even for rather hydrophobic ligands to bind in the active site groove, which is promising for the application of similar soaking experiments to less robust crystals of other proteins.

AB - The 1.8 Å resolution de novo structure of nucleoside 2-deoxyribosyltransferase (EC 2.4.2.6) from Trypanosoma brucei (TbNDRT) has been determined by SAD phasing in an unliganded state and several ligand-bound states. This enzyme is important in the salvage pathway of nucleoside recycling. To identify novel lead compounds, we exploited "fragment cocktail soaks". Out of 304 compounds tried in 31 cocktails, four compounds could be identified crystallographically in the active site. In addition, we demonstrated that very short soaks of ∼10 s are sufficient even for rather hydrophobic ligands to bind in the active site groove, which is promising for the application of similar soaking experiments to less robust crystals of other proteins.

UR - http://www.scopus.com/inward/record.url?scp=33749262286&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33749262286&partnerID=8YFLogxK

U2 - 10.1021/jm060429m

DO - 10.1021/jm060429m

M3 - Article

C2 - 17004709

AN - SCOPUS:33749262286

SN - 0022-2623

VL - 49

SP - 5939

EP - 5946

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 20

ER -

Using fragment cocktail crystallography to assist inhibitor design of Trypanosoma brucei nucleoside 2-deoxyribosyltransferase

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this