bims-lowpac 2023-12-17 papers

Issue of 2023–12–17
two papers selected by
Elodie Busch, University of Strasbourg

Molecules. 2023 Nov 25. pii: 7774. [Epub ahead of print]28(23):

Determination and Kinetic Characterization of a New Potential Inhibitor for AmsI Protein Tyrosine Phosphatase from the Apple Pathogen Erwinia amylovora.

Simone Albani, Ivan Polsinelli, Luca Mazzei, Francesco Musiani, Stefano Benini.

Erwinia amylovora is a Gram-negative bacterium, responsible for the fire blight disease in Rosaceae plants. Its virulence is correlated with the production of an exopolysaccharide (EPS) called amylovoran, which protects the bacterium from the surrounding environment and helps its diffusion inside the host. Amylovoran biosynthesis relies on the expression of twelve genes clustered in the ams operon. One of these genes, amsI, encodes for a Low Molecular Weight Protein Tyrosine Phosphatase (LMW-PTP) called EaAmsI, which plays a key role in the regulation of the EPS production pathway. For this reason, EaAmsI was chosen in this work as a target for the development of new antibacterial agents against E. amylovora. To achieve this aim, a set of programs (DOCK6, OpenEye FRED) was selected to perform a virtual screening using a database of ca. 700 molecules. The six best-scoring compounds identified were tested in in vitro assays. A complete inhibition kinetic characterization carried out on the most promising molecule (n-Heptyl β-D-glucopyranoside, N7G) showed an inhibition constant of 7.8 ± 0.6 µM. This study represents an initial step towards the development of new EaAmsI inhibitors able to act as antibacterial agents against E. amylovora infections.

Keywords: EPS production regulation; Erwinia amylovora; amylovoran; exopolysaccharide; fire blight; in vitro assays; inhibition constant; molecular docking; protein tyrosine phosphatase; virtual screening

DOI: https://doi.org/10.3390/molecules28237774

Chimia (Aarau). 2022 May 25. 76(5): 460-465

Protein Phosphatases: A Neglected Target Family for Drug Discovery.

Joe Lewis, Gerhard Müller.

The gene family of protein phosphatases is a rich but under-exploited source of therapeutically validated drug targets modulating signal transduction pathways. Unlike the kinase family, research and development activities have not yet yielded any approved small-molecule drugs against a phosphatase. Approximately 20 years ago, the phosphatase family was classified as undruggable and intractable. This was primarily due to the spectacular failure of the cumulated industry-wide drug discovery efforts to develop PTP1B inhibitors. Recently, allosteric inhibitors against SHP2, a member of the phosphatase family, have entered clinical trails, which has reawakened industry's interest towards this neglected enzyme family. This contribution reviews the recent R&D trends around small-molecule efforts towards phosphatase modulators over the last years, rather than providing an exhaustive review of the field of allosteric phosphatase inhibitors.

Keywords: Allosteric inhibitors; Inhibitors; Kinases; PTP1B; Phosphatases; SHP2; Target family

DOI: https://doi.org/10.2533/chimia.2022.460