Discovery of Novel Chemical Series of OXA-48 β-Lactamase Inhibitors by High-Throughput Screening.

The major cause of bacterial resistance to β-lactams is the production of hydrolytic β-lactamase enzymes. Nowadays, the combination of β-lactam antibiotics with β-lactamase inhibitors (BLIs) is the main strategy for overcoming such issues. Nevertheless, particularly challenging β-lactamases, such as OXA-48, pose the need for novel and effective treatments.

Optimization of Indazole-Based GSK-3 Inhibitors with Mitigated hERG Issue and Activity in a Mood Disorder Model.

Bipolar disorders still represent a global unmet medical need and pose a requirement for novel effective treatments. In this respect, glycogen synthase kinase 3β (GSK-3β) aberrant activity has been linked to the pathophysiology of several disease conditions, including mood disorders. Therefore, the development of GSK-3β inhibitors with good efficacy and safety profile associated with high brain exposure is required.

Discovery of Novel Imidazopyridine GSK-3β Inhibitors Supported by Computational Approaches.

The interest of research groups and pharmaceutical companies to discover novel GSK-3β inhibitors has increased over the years considering the involvement of this enzyme in many pathophysiological processes and diseases. Along this line, we recently reported on 1H-indazole-3-carboxamide (INDZ) derivatives -, showing good GSK-3β inhibition activity. However, they suffered from generally poor central nervous system (CNS) permeability.

Molecular basis for the different interactions of congeneric substrates with the polyspecific transporter AcrB.

The drug/proton antiporter AcrB, which is part of the major efflux pump AcrABZ-TolC in Escherichia coli, is the paradigm transporter of the resistance-nodulation-cell division (RND) superfamily. Despite the impressive ability of AcrB to transport many chemically unrelated compounds, only a few of these ligands have been co-crystallized with the protein. Therefore, the molecular features that distinguish good substrates of the pump from poor ones have remained poorly understood to date.

Secondary metabolites from cetrarioid lichens: Chemotaxonomy, biological activities and pharmaceutical potential.

Background: Lichens, as a symbiotic association of photobionts and mycobionts, display an unmatched environmental adaptability and a great chemical diversity. As an important morphological group, cetrarioid lichens are one of the most studied lichen taxa for their phylogeny, secondary chemistry, bioactivities and uses in folk medicines, especially the lichen Cetraria islandica. However, insufficient structure elucidation and discrepancy in bioactivity results could be found in a few studies.

Investigating Pharmacological Similarity by Charting Chemical Space.

In this study, biologically relevant areas of the chemical space were analyzed using ChemGPS-NP. This application enables comparing groups of ligands within a multidimensional space based on principle components derived from physicochemical descriptors. Also, 3D visualization of the ChemGPS-NP global map can be used to conveniently evaluate bioactive compound similarity and visually distinguish between different types or groups of compounds.

Identification of N-acylhydrazone derivatives as novel lactate dehydrogenase A inhibitors.

Glycolysis is drastically increased in tumors and it is the main route to energy production with a minor use of oxidative phosphorylation. Among the key enzymes in the glycolytic process, LDH is emerging as one of the most interesting targets for the development of new inhibitors. In this context, in the present work, we carried out a virtual screening procedure followed by chemical modifications of the identified structures according to a "hit-to-lead" process.

Protein Flexibility in Drug Discovery: From Theory to Computation.

Nowadays it is widely accepted that the mechanisms of biomolecular recognition are strongly coupled to the intrinsic dynamic of proteins. In past years, this evidence has prompted the development of theoretical models of recognition able to describe ligand binding assisted by protein conformational changes. On a different perspective, the need to take into account protein flexibility in structure-based drug discovery has stimulated the development of several and extremely diversified computational methods.

A ligand-based virtual screening approach to identify small molecules as HERG channel activators.

The hERG potassium channel is currently emerging as a potential target for the treatment of some forms of arrhythmias or to contrast an unintentional channel block caused by drugs. Despite its therapeutic relevance, so far only few compounds are described as able to enhance channel function by potentiating hERG currents. This gap is also related to the lack of hERG crystal structure which strongly limits the possibility to employ structure-based techniques in the search and design of novel activators.

Collecting and assessing human lactate dehydrogenase-A conformations for structure-based virtual screening.

Human lactate dehydrogenase-A (LDHA) is emerging as a promising anticancer target. Up to now, structure-based investigations for identifying inhibitors of this enzyme have not explicitly accounted for active site flexibility. In the present study, by combining replica exchange molecular dynamics with network and cluster analyses, we identified reliable LDHA conformations for structure-based ligand design.

Computational design and discovery of "minimally structured" hERG blockers.

Molecular knowledge of hERG blocking liability can offer the possibility of optimizing lead compounds in a way that eliminates potentially lethal side effects. In this study, we computationally designed, synthesized, and tested a small series of "minimally structured" molecules. Some of these compounds were remarkably potent against hERG (6, IC(50) = 2.

Galloflavin (CAS 568-80-9): a novel inhibitor of lactate dehydrogenase.

One of the most prominent alterations in cancer cells is their strict dependence on the glycolytic pathway for ATP generation. This observation led to the evaluation of glycolysis inhibitors as potential anticancer agents. The inhibition of lactate dehydrogenase (LDH) is a promising way to inhibit tumor cell glucose metabolism without affecting the energetic balance of normal tissues.