Abstract
Chorismate-utilizing enzymes are attractive antimicrobial drug targets due to their absence in humans and their central role in bacterial survival and virulence. The structural and mechanistic homology of a group of these inspired the goal of discovering inhibitors that target multiple enzymes. Previously, we discovered seven inhibitors of 4-amino-4-deoxychorismate synthase (ADCS) in an on-bead, fluorescent-based screen of a 2304-member one-bead-one-compound combinatorial library. The inhibitors comprise PAYLOAD and COMBI stages, which interact with active site and surface residues, respectively, and are linked by a SPACER stage. These seven compounds, and six derivatives thereof, also inhibit two other enzymes in this family, isochorismate synthase (IS) and anthranilate synthase (AS). The best binding compound inhibits ADCS, IS, and AS with K i values of 720, 56, and 80 μM, respectively. Inhibitors with varying SPACER lengths show the original choice of lysine to be optimal. Lastly, inhibition data confirm the PAYLOAD stage directs the inhibitors to the ADCS active site.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 3718-3729 |
| Number of pages | 12 |
| Journal | Journal of Medicinal Chemistry |
| Volume | 53 |
| Issue number | 9 |
| DOIs | |
| State | Published - May 13 2010 |
Fingerprint
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery
Cite this
Targeting multiple chorismate-utilizing enzymes with a single inhibitor : Validation of a three-stage design. / Ziebart, Kristin T.; Dixon, Seth M.; Avila, Belem; El-Badri, Mohamed H.; Guggenheim, Kathryn G.; Kurth, Mark J.; Toney, Michael D.
In: Journal of Medicinal Chemistry, Vol. 53, No. 9, 13.05.2010, p. 3718-3729.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Targeting multiple chorismate-utilizing enzymes with a single inhibitor
T2 - Validation of a three-stage design
AU - Ziebart, Kristin T.
AU - Dixon, Seth M.
AU - Avila, Belem
AU - El-Badri, Mohamed H.
AU - Guggenheim, Kathryn G.
AU - Kurth, Mark J.
AU - Toney, Michael D.
PY - 2010/5/13
Y1 - 2010/5/13
N2 - Chorismate-utilizing enzymes are attractive antimicrobial drug targets due to their absence in humans and their central role in bacterial survival and virulence. The structural and mechanistic homology of a group of these inspired the goal of discovering inhibitors that target multiple enzymes. Previously, we discovered seven inhibitors of 4-amino-4-deoxychorismate synthase (ADCS) in an on-bead, fluorescent-based screen of a 2304-member one-bead-one-compound combinatorial library. The inhibitors comprise PAYLOAD and COMBI stages, which interact with active site and surface residues, respectively, and are linked by a SPACER stage. These seven compounds, and six derivatives thereof, also inhibit two other enzymes in this family, isochorismate synthase (IS) and anthranilate synthase (AS). The best binding compound inhibits ADCS, IS, and AS with K i values of 720, 56, and 80 μM, respectively. Inhibitors with varying SPACER lengths show the original choice of lysine to be optimal. Lastly, inhibition data confirm the PAYLOAD stage directs the inhibitors to the ADCS active site.
AB - Chorismate-utilizing enzymes are attractive antimicrobial drug targets due to their absence in humans and their central role in bacterial survival and virulence. The structural and mechanistic homology of a group of these inspired the goal of discovering inhibitors that target multiple enzymes. Previously, we discovered seven inhibitors of 4-amino-4-deoxychorismate synthase (ADCS) in an on-bead, fluorescent-based screen of a 2304-member one-bead-one-compound combinatorial library. The inhibitors comprise PAYLOAD and COMBI stages, which interact with active site and surface residues, respectively, and are linked by a SPACER stage. These seven compounds, and six derivatives thereof, also inhibit two other enzymes in this family, isochorismate synthase (IS) and anthranilate synthase (AS). The best binding compound inhibits ADCS, IS, and AS with K i values of 720, 56, and 80 μM, respectively. Inhibitors with varying SPACER lengths show the original choice of lysine to be optimal. Lastly, inhibition data confirm the PAYLOAD stage directs the inhibitors to the ADCS active site.
UR - http://www.scopus.com/inward/record.url?scp=77952044139&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=77952044139&partnerID=8YFLogxK
U2 - 10.1021/jm100158v
DO - 10.1021/jm100158v
M3 - Article
C2 - 20359225
AN - SCOPUS:77952044139
VL - 53
SP - 3718
EP - 3729
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 9
ER -