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Dihydroceramide desaturase 1 (Des1) catalyzes the formation of a CC double bond in dihydroceramide to furnish ceramide. Inhibition of Des1 is related to cell cycle arrest and programmed cell death. The lack of the Des1 crystalline structure, as well as that of a close homologue, hampers the detailed understanding of its inhibition mechanism and difficults the design of new inhibitors, thus making Des1 a strategic target. Based on previous structure-activity studies, different ceramides containing rigid scaffolds were designed. The synthesis and evaluation of these compounds as Des1 inhibitors allowed the identification of PR280 as a better Des 1 inhibitor in vitro (IC50 = 700 nM) than GT11 and XM462, the current reference inhibitors. This cyclopropenone ceramide was obtained in a 6-step synthesis with a 24 % overall yield. The highly confident 3D structure of Des1, recently predicted by AlphaFold2, served as the basis for conducting docking studies of known Des1 inhibitors and the ceramide derivatives synthesized by us in this study. For this purpose, a complete holoprotein structure was previously constructed. This study has allowed a better knowledge of key ligand-enzyme interactions for Des1 inhibitory activity. Furthermore, it sheds some light on the inhibition mechanism of GT11.Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.

Continuum solvation models like PCM or COSMO are the standard tool to calculate solvation free energies in a quantum level, but have been typically limited to small biological molecules due to its large computational cost. Recently, a new implementation of COSMO based on a domain decomposition strategy (ddCOSMO) [1] has been presented, which speeds up calculations by several orders of magnitude, thus paving the way for its application to very large systems. Here, we report the parameterization of ddCOSMO to the prediction of hydration free energies based on the MST solvation model developed in Barcelona, [2][3]. The parameterization is based on the PM6 semi-empirical Hamiltonian, on a set of over 200 experimental hydration free energies. The new model opens the way to the accurate prediction of hydration free energies of very large biomolecules, thus going beyond the usual classical MM-PBSA or MM-GBSA approaches.

Using a commercial instrument that integrates microfluidics with surface plasmon resonance (SPR) detection, we thermodynamically and kinetically characterise the interactions of water-soluble calix[4]pyrroles with surface-immobilized guests derived from pyridine N-oxide. This technique provides detailed information in real time and shows that, while thermodynamically similar, the binding process occurring with the surface-immobilised guests is kinetically very different to that in solution. Two different binding processes can be distinguished for the surface-immobilised guests. Both complexation processes provide 1:1 complexes with thermodynamic stabilities that are similar to each other and to the 1:1 complex formed in solution. However, the kinetic stabilities of the complexes formed with the surface anchored ligands are significantly higher. These observations are rationalized on the basis of the effects exerted by the dextran matrix employed for the ligand's immobilisation on the small molecule complexes that are formed. This journal is © the Partner Organisations 2014.

Using a commercial instrument that integrates microfluidics with surface plasmon resonance (SPR) detection, we thermodynamically and kinetically characterise the interactions of water-soluble calix4pyrroles with surface-immobilized guests derived from pyridine N-oxide. This technique provides detailed information in real time and shows that, while thermodynamically similar, the binding process occurring with the surface-immobilised guests is kinetically very different to that in solution. Two different binding processes can be distinguished for the surface-immobilised guests. Both complexation processes provide 1:1 complexes with thermodynamic stabilities that are similar to each other and to the 1:1 complex formed in solution. However, the kinetic stabilities of the complexes formed with the surface anchored ligands are significantly higher. These observations are rationalized on the basis of the effects exerted by the dextran matrix employed for the ligand's immobilisation on the small molecule complexes that are formed. This journal is © the Partner Organisations 2014.