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Never Gonna Give You Up – Current Developments in Covalent Protein Kinase Inhibitors
Get PDFCovalent inhibitors have recently seen a revival in medicinal chemistry. Inhibitors addressing non-catalytic cysteine residues with weakly reactive electrophiles have been very successfully employed to target protein kinases, one of the major druggable protein families. Here we provide an overview of irreversible and reversible covalent protein kinase inhibitors in clinical development and beyond. We further spotlight recent advances in targeting amino acids other than cysteine and the reactive groups utilized in covalent protein kinase inhibitors
Reverse Design toward Optimized Labeled Chemical Probes – Examples from the Endocannabinoid System
Get PDFLabeled chemical probes are of utmost importance to bring drugs from the laboratory through the clinic and ultimately to market. They support and impact all research and discovery phases: target verification and validation; assay development; lead optimization; and biomarker engagement in the context of preclinical studies and human trials. Probes should display high potency and selectivity as well as fulfill specific criteria in connection with absorption, distribution, metabolism, excretion and toxicology (ADMET) profile. Progress in fields such as imaging and proteomics increased the need for specialized probes to support drug discovery. Labeled probes carrying an additional reporter group are valuable tools to meet specific application requirements, but pose significant challenges in design and construction. In the reverse-design approach, small molecules previously optimized in medicinal chemistry programs form the basis for the generation of such high-quality probes. We discuss the reverse design concept for the generation of labeled probes targeting the endocannabinoid system (ECS), a complex lipid signaling network that plays a key role in many human health and disease conditions. The examples highlighted include diverse reporter units for a range of applications. In several cases the reported probes were the product of mutually rewarding and highly cross-fertilizing collaborations among academic and industry research programs, a strategy that can serve as a blueprint for future probe generation efforts
Efficient Semiclassical Evaluation of Electronic Coherences in Polyatomic Molecules
Get PDFExposing a molecule to intense light pulses may bring this molecule to a nonstationary quantum state, thus launching correlated dynamics of electronic and nuclear subsystems. Although much had been achieved in the understanding of fundamental physics behind the electron-nuclear interactions and dynamics, accurate numerical simulations of light-induced processes taking place in polyatomic molecules remain a formidable challenge. Here, we review a recently developed theoretical approach for evaluating electronic coherences in molecules, in which the ultrafast electronic dynamics is coupled to nuclear motion. The presented technique, which combines accurate ab initio on-the-fly simulations of electronic structure with efficient semiclassical procedure to compute the dynamics of nuclear wave packets, is not only computationally efficient, but also can help shed light on the underlying physical mechanisms of decoherence and revival of the electronic coherences driven by nuclear rearrangement
Protein Phosphatases: A Neglected Target Family for Drug Discovery
Get PDFThe 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
A New Approach for Identifying Positional Isomers of Glycans Cleaved from Monoclonal Antibodies: Highlights of Analytical Sciences in Switzerland
No full textDMCCB Basel Symposium 2022: Intrinsically Disordered Proteins as Drug Targets, Online, 31st January, 2022: Conference Report
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Units – Student’s Friend or Fiend? Chemical Education
No full textThe idea beyond this column is to point out the difficulties that students or pupils often have when solving problems that require handling units. These include the use of the proper unit for the corresponding physical quantity during the calculation, analysis of the units and providing the result as a numerical value with a correct unit. A wish to join the efforts of all teachers to solve this problem is also expressed