ML025 : AmpC (E. Coli AmpC β-Lactamase) Inhibitor
ML025
Target Name
E. Coli AmpC β-Lactamase
Target Alias
AmpC
Target Class
Hydrolase
Mechanism of Action
Inhibitor of AmpC
Biological / Disease Relevance
AmpC beta-lactamase pathway
In vitro activity
IC50Inactive Control
Available
Target Information
AmpC β-lactamases mostly are cephalosporinases but are capable of hydrolysing all β-lactams to some extent. The hydrolytic properties of AmpC ß-lactamases are similar. Unfortunately, these enzymes have demonstrated drug resistant properties for the third generation cephalosporins presenting immense future challenges to health providers. As such, we explored a screen and optimization program for novel inhibitors (both covalent and non-covalent) of this enzyme class. Covalent inhibitor refers to chemotype 2 of this enzyme class.
Properties
ML025
NCGC00067552
| Physical & chemical properties | ||||
|---|---|---|---|---|
| Molecular Weight | 436.3 g/mol | |||
| Molecular Formula | C16H19Cl2N3O5S | |||
| cLogP | 1.73 | |||
| PSA | 111.39 | |||
| Storage | ||||
| Solubility | Up to 10mM in DMSO | |||
| CAS Number | ||||
SMILES:
CC(C)(OC(NCCC1=NN=C(S(=O)(CC2=C(Cl)C=C(Cl)C=C2)=O)O1)=O)C
InChI:
InChI=1S/C16H19Cl2N3O5S/c1-16(2,3)26-14(22)19-7-6-13-20-21-15(25-13)27(23,24)9-10-4-5-11(17)8-12(10)18/h4-5,8H,6-7,9H2,1-3H3,(H,19,22)
InChIKey:
KTPSEIKHZBDCBJ-UHFFFAOYSA-N
Activity
Summary activity statement /
ML025 (CID 665449, SID 864201) is observed to be a potent and selective inhibitor of AmpC beta-lactamase. This compound was found to inhibit AmpC in a detergent insensitive manner at high potencies. In collaboration with Professor Brian Shoichet, this agent was among the 1274 actives that were characterized by secondary assays, mass analysis, and co-crystallization studies. While the majority of these compounds were found to be detergent sensitive colloidal aggregates, ML025 (SID: 864201) was noted to be a covalent modifier of AmpC based upon mass analysis (AmpC was noted to increase in mass by 240.1 AMU). Further, the exact mechanism of covalent modification was determined through co-crystallization studies with the enzyme. This compound represents an important new chemotype for AmpC inhibition (Babaoglu, 2008).
In vitro Assay - Selectivity
| ML025 IC50 (uM) | |
|---|---|
|
AmpC beta-lactamase |
0.066 |
|
Cruzain |
410 |
|
Chym |
>1 |
|
MDH |
0.600 |
Summary /
ML025 is screened against 3 other targets to evaluate selectivity. It is 6200-fold more potent against AmpC beta-lactamse than against Cruzain; 15-fold more potent than against Chym; and 9-fold than against MDH.
In vitro Assay - Co-crystallization studies
Summary /
Figure 1. A. Structure of ML025 (SID 864201) with fragment mass = 240. B. Crystal structure showing the portion of the molecule that covalently modifies AmpC.