Identification of specific carbonic anhydrase inhibitors click chemistry, phage-display and synthetic peptide libraries: comparison of the methods and structural study.

The development of highly active and selective enzyme inhibitors is one of the priorities of medicinal chemistry. Typically, various high-throughput screening methods are used to find lead compounds from a large pool of synthetic compounds, and these are further elaborated and structurally refined to achieve the desired properties. In an effort to streamline this complex and laborious process, new selection strategies based on different principles have recently emerged as an alternative.

Kinetic Target-Guided Synthesis of Small-Molecule G-Quadruplex Stabilizers.

The formation of a G-quadruplex motif in the promoter region of the protooncogene prevents its expression. Accordingly, G-quadruplex stabilization by a suitable ligand may be a viable approach for anticancer therapy. In our study, we used the 4-(4-methylpiperazin-1-yl)aniline molecule, previously identified as a fragment library screen hit, as a template for the SAR-guided design of a new small library of clickable fragments and subjected them to click reactions, including kinetic target-guided synthesis in the presence of a G-quadruplex forming oligonucleotide Pu24.

GTP-Dependent Formation of Multimeric G-Quadruplexes.

G-Quadruplexes are noncanonical nucleic acid structures made up of stacked guanosine tetrads connected by short loops. They are frequently used building blocks in synthetic biology and thought to play widespread biological roles. Multimerization can change the functional properties of G-quadruplexes, and understanding the factors that modulate this process remains an important goal.

Rearrangement of meta-Bridged Calix[4]arenes Promoted by Internal Strain.

The meta-bridged calixarenes possess a rigidified and highly distorted cavity, where the additional single-bond bridge imposes an extreme internal strain on the whole system. As a consequence, these compounds exhibit a reasonably amended reactivity, compared with common calix[4]arene derivatives, which is governed by the release of internal strain. This can be documented by the reaction of the bridged calix[4]arene with PO or Nafion-H, leading (apart from polymers) to a macrocyclic product with a rearranged basic skeleton.

PI(4,5)P controls plasma membrane PI4P and PS levels via ORP5/8 recruitment to ER-PM contact sites.

Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P) is a critically important regulatory lipid of the plasma membrane (PM); however, little is known about how cells regulate PM PI(4,5)P levels. Here, we show that the phosphatidylinositol 4-phosphate (PI4P)/phosphatidylserine (PS) transfer activity of the endoplasmic reticulum (ER)-resident ORP5 and ORP8 is regulated by both PM PI4P and PI(4,5)P Dynamic control of ORP5/8 recruitment to the PM occurs through interactions with the N-terminal Pleckstrin homology domains and adjacent basic residues of ORP5/8 with both PI4P and PI(4,5)P Although ORP5 activity requires normal levels of these inositides, ORP8 is called on only when PI(4,5)P levels are increased. Regulation of the ORP5/8 attachment to the PM by both phosphoinositides provides a powerful means to determine the relative flux of PI4P toward the ER for PS transport and Sac1-mediated dephosphorylation and PIP 5-kinase-mediated conversion to PI(4,5)P Using this rheostat, cells can maintain PI(4,5)P levels by adjusting the availability of PI4P in the PM.

Ranking Power of the SQM/COSMO Scoring Function on Carbonic Anhydrase II-Inhibitor Complexes.

Accurate prediction of protein-ligand binding affinities is essential for hit-to-lead optimization and virtual screening. The reliability of scoring functions can be improved by including quantum effects. Here, we demonstrate the ranking power of the semiempirical quantum mechanics (SQM)/implicit solvent (COSMO) scoring function by using a challenging set of 10 inhibitors binding to carbonic anhydrase II through Zn in the active site.

Oligomeric interface modulation causes misregulation of purine 5´-nucleotidase in relapsed leukemia.

Background: Relapsed acute lymphoblastic leukemia (ALL) is one of the main causes of mortality in childhood malignancies. Previous genetic studies demonstrated that chemoresistant ALL is driven by activating mutations in NT5C2, the gene encoding cytosolic 5´-nucleotidase (cN-II). However, molecular mechanisms underlying this hyperactivation are still unknown.

Use of residual dipolar couplings in conformational analysis of meta-disubstituted calix[4]arenes.

Dimercuration of tetrapropoxy calix[4]arene followed by a reaction with isoamyl nitrite afforded dinitroso regioisomers with unique substitution patterns. The unusual conformational behaviour of these inherently chiral systems was revealed by the combination of dynamic NMR and residual dipolar coupling (RDC) techniques.

Calix[4]arenes with intramolecularly bridged meta positions prepared via Pd-catalysed double C-H activation.

The introduction of a 2-pyridylsulfoxide moiety into the upper rim of calix[4]arenes enabled the synthesis of unprecedented derivatives with intramolecularly bridged meta positions of two neighbouring aromatic subunits. Palladium-catalysed double C-H activation thus represents a straightforward way to a completely novel type of calixarenes.