Description
The shikimate pathway is a de novo biosynthetic route for aromatic compounds. Due to its importance in fungi, plants, and bacteria and its absence in mammals it was already earlier confirmed by glyphosate as a promising target for developing antimicrobial and herbicide agents. The last reaction of this pathway is catalyzed by chorismate synthase (CS), which involves an unusual elimination reaction making it an attractive target for our research. A homology model of CS from Paracoccidioides brasiliensis (PbCS) was used in previous inhibitor screening efforts, and based on the best hit, nitrazine yellow, we tested a series of azo-dyes for their inhibitory potential against PbCS. The most promising candidate was the azo-dye PH011669, exhibiting a binding affinity (Kd) toward PbCS of 1.1 ± 0.1 µM and a 50 % inhibitory constant (IC50) of 10 ± 1 µM. An AlphaFold model of PbCS was used to study the binding mode of PH011669 by molecular docking and MD simulations. Our in-silico results unveiled that PH011669 binding is governed by electrostatic interactions between the inhibitor’s negatively charged sulfonate groups and the enzyme’s positively charged arginine residues, which represent the binding hot spots in CS. The obtained in-silico information will guide the optimization of the inhibitor’s binding affinity and chemical absorption, distribution, metabolism, excretion, and toxicity (ADMET) properties. Thus, our study may help develop novel antimicrobial and antifungal agents targeting CS.| Period | 15 Jul 2024 → 19 Jul 2024 |
|---|---|
| Event title | 21st International Flavins and Flavoproteins Symposium |
| Event type | Conference |
| Location | Atlanta, United StatesShow on map |
| Degree of Recognition | International |
Keywords
- flavin
- flavoprotein