Abstract
In the 1950s, Bernhard Davis and David Sprinson discovered a biosynthetic route to the
aromatic amino acids phenylalanine, tryptophan, and tyrosine. As this metabolic
pathway is only present in prokaryotes, fungi, and plants, mammals need to get aromatic
amino acids from their diet.
The inhibition of this pathway can eventually lead to cell death because each step of the
shikimate pathway comprises an essential reaction in chorismate synthesis, which
cannot be bypassed by any alternative enzyme. This knowledge makes the shikimate
pathway a promising target for the development of antibacterial agents and herbicides.
From the seven enzymes of the pathway, chorismate synthase (CS) was chosen as a drug
target because of its unique catalytic mechanism. Suitable CS inhibitors were selected
using a combination of virtual screening and molecular dynamics performed by Seixas
and co workers [1,2].
Various methods were used to investigate the interaction of the enzymes and the
obtained inhibitory compounds. Among other parameters, dissociation constants
(1.1-4.4 μM) and IC50 values (10-16 μM) were determined by using a binding and
inhibition assay, respectively. To get a better insight into the binding mode,
crystallization of CS-inhibitor complexes is under progress.
Binding of the inhibitory compound to the enzymes could be confirmed, whereby the
class of azo-dyes turned out to be a promising group of antifungal drugs. To improve the
binding of the inhibitory compounds to CSs the active site will be investigated in more
detail. Nevertheless, a crystal structure of an enzyme-inhibitor complex is required to
design new compounds with improved binding affinity (nm-range).
References
[1] Rodrigues-Vendramini et al. (2018), Promising New Antifungal Treatment Targeting Chorismate
Synthase from Paracoccidioides brasiliensis, Antimicrobial Agents and Chemotherapy 63 (1).
[2] Bueno et al (2019), New inhibitors of chorismate synthase present antifungal activity against
Paracoccidioides brasiliensis, Future Microbiology 14 (11): 969-980.
28
aromatic amino acids phenylalanine, tryptophan, and tyrosine. As this metabolic
pathway is only present in prokaryotes, fungi, and plants, mammals need to get aromatic
amino acids from their diet.
The inhibition of this pathway can eventually lead to cell death because each step of the
shikimate pathway comprises an essential reaction in chorismate synthesis, which
cannot be bypassed by any alternative enzyme. This knowledge makes the shikimate
pathway a promising target for the development of antibacterial agents and herbicides.
From the seven enzymes of the pathway, chorismate synthase (CS) was chosen as a drug
target because of its unique catalytic mechanism. Suitable CS inhibitors were selected
using a combination of virtual screening and molecular dynamics performed by Seixas
and co workers [1,2].
Various methods were used to investigate the interaction of the enzymes and the
obtained inhibitory compounds. Among other parameters, dissociation constants
(1.1-4.4 μM) and IC50 values (10-16 μM) were determined by using a binding and
inhibition assay, respectively. To get a better insight into the binding mode,
crystallization of CS-inhibitor complexes is under progress.
Binding of the inhibitory compound to the enzymes could be confirmed, whereby the
class of azo-dyes turned out to be a promising group of antifungal drugs. To improve the
binding of the inhibitory compounds to CSs the active site will be investigated in more
detail. Nevertheless, a crystal structure of an enzyme-inhibitor complex is required to
design new compounds with improved binding affinity (nm-range).
References
[1] Rodrigues-Vendramini et al. (2018), Promising New Antifungal Treatment Targeting Chorismate
Synthase from Paracoccidioides brasiliensis, Antimicrobial Agents and Chemotherapy 63 (1).
[2] Bueno et al (2019), New inhibitors of chorismate synthase present antifungal activity against
Paracoccidioides brasiliensis, Future Microbiology 14 (11): 969-980.
28
| Translated title of the contribution | Die Chorismatsynthase als Arzneimittel Zielobjekt |
|---|---|
| Original language | English |
| Publication status | Published - 7 Jul 2022 |
| Event | 27th NAWI Graz DocDay - Graz University, Graz, Austria Duration: 7 Jul 2022 → … |
Seminar
| Seminar | 27th NAWI Graz DocDay |
|---|---|
| Country/Territory | Austria |
| City | Graz |
| Period | 7/07/22 → … |
| Other | 27th DocDay NAWI Graz Doctoral School of Molecular Biosciences and Biotechnology |