Inverse PI by NMR: Analysis of Ligand 1H-Chemical Shifts in the Protein-Bound State

The study of protein-ligand interactions via protein-based NMR generally relies on the detection of chemical-shift changes induced by ligand binding. However, the chemical shift of the ligand when bound to the protein is rarely discussed, since it is not readily detectable. In this work we use protein deuteration in combination with [1H-1H]-NOESY NMR to extract 1H chemical shift values of the ligand in the bound state. The chemical shift perturbations (CSPs) experienced by the proton ligand resonances (free vs bound) are an extremely rich source of information on protein-ligand complexes. Besides allowing for the detection of intermolecular CH-π interactions and elucidation of the protein-bound ligand conformation, the CSP information can be used to analyse (de)solvation effects in a site-specific manner. In conjunction with crystal structure information, it is possible to distinguish protons whose desolvation penalty is compensated for upon protein-binding, from those that are not. Combined with the previously reported PI by NMR technique for the protein-based detection of intermolecular CH-π interactions, this method represents another important step towards the ultimate goal of Interaction-Based Drug Discovery.

Synthesis and structures of three new pyridine-containing oxazoline ligands of complexes for asymmetric catalysis

Three new chiral pyridine-containing oxazoline derivatives with fluorine and perfluoromethyl groups, namely, 2-({2-[(4S)-4-phenyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}amino)-5-(trifluoromethyl)pyridine, C21H16F3N3O, 2-({5-fluoro-2-[(4S)-4-isopropyl-4,5-dihydro-1,3-oxazol-2-yl]phenyl}amino)-5-(trifluoromethyl)pyridine, C18H17F4N3O, and 2-({2-[(3aR,8aS)-8,8a-dihydro-3aH-indeno[1,2-d]oxazol-2-yl]phenyl}amino)-5-(trifluoromethyl)pyridine, C22H16F3N3O, as chiral ligands in metal-catalysed asymmetric reactions, were synthesized and characterized by spectral and X-ray diffraction methods. The conformation of the molecules is influenced by strong N—H...N hydrogen bonding and weak C—H...X (X = O and N) interactions. There are no intermolecular hydrogen bonds in the crystal structures of the analysed compounds. Hirshfeld surface analysis showed that the H...H contacts constitute a high percentage of the intermolecular interactions. The conformational analysis was performed by theoretical calculations using the density functional theory (DFT) method. The mechanism of complex formation in terms of the electron-withdrawing effect of the substituents on the oxazoline ring and the ligand conformation is discussed.

Two Decades of 4D-QSAR: A Dying Art or Staging a Comeback?

A key question confronting computational chemists concerns the preferable ligand geometry that fits complementarily into the receptor pocket. Typically, the postulated ‘bioactive’ 3D ligand conformation is constructed as a ‘sophisticated guess’ (unnecessarily geometry-optimized) mirroring the pharmacophore hypothesis—sometimes based on an erroneous prerequisite. Hence, 4D-QSAR scheme and its ‘dialects’ have been practically implemented as higher level of model abstraction that allows the examination of the multiple molecular conformation, orientation and protonation representation, respectively. Nearly a quarter of a century has passed since the eminent work of Hopfinger appeared on the stage; therefore the natural question occurs whether 4D-QSAR approach is still appealing to the scientific community? With no intention to be comprehensive, a review of the current state of art in the field of receptor-independent (RI) and receptor-dependent (RD) 4D-QSAR methodology is provided with a brief examination of the ‘mainstream’ algorithms. In fact, a myriad of 4D-QSAR methods have been implemented and applied practically for a diverse range of molecules. It seems that, 4D-QSAR approach has been experiencing a promising renaissance of interests that might be fuelled by the rising power of the graphics processing unit (GPU) clusters applied to full-atom MD-based simulations of the protein-ligand complexes.

Counterion Effect and Isostructurality in a Series of Ag(I) Complexes Containing a Flexible, Imidazole Based Dipodal Ligand

The crystal structures of a series of Ag(I) complexes with 1,3-bis(imidazol-1-ylmethyl)-5-methylbenzene (L) and the counterions BF4− (1), PF6− (2), ClO4− (3), and CF3SO3− (4) were analysed to determine the effect of the latter on their formation. All resulting compounds crystallise in the non-centrosymmetric space group Cc of a monoclinic system and show the formation of cationic, polymeric 1D Ag(I) complexes. SCXRD analyses revealed that compounds 1–3 are isostructural, though 1 shows opposite handedness compared to 2 and 3, resulting in an inversed packing arrangement. The presence of the larger, elongated triflate counterion in 4 leads to a different ligand conformation, as well as different arrangements of the ligand in the cationic chain, and simultaneously results in a packing that exhibits fewer similarities with the remaining three compounds.

Engineering ligand conformation by substituent manipulation towards diverse copper–tricarboxylate frameworks with tuned gas adsorption properties

Two copper–tricarboxylate frameworks with diverse topologies were targeted by engineering the ligand conformations, displaying tunable gas adsorption properties.

Insilico analysis of acridone against TNF-α and PDE4 targets for the treatment of psoriasis

Psoriasis is an autoimmune disorder. Phosphodiesterase is a family of 1-11 among which PDE4 is most predominant enzymes present in inflammatory cells. Commercially available drugs are synthetic, and these may cause various side effects and are expensive. Dimethyl fumarate is the most frequently used systematic treatment for psoriasis with significant side effects such as myelosuppression, hepatic fibrosis and pulmonary fibrosis. Immune compromise drugs having various side effects, so this project is aimed to propose a novel drug that has more potency, efficiency and least side effects. The docking analysis was carried out to identify the best ligands by predicting the ligand conformation in the active protein sites and ligand binding affinity towards protein. Ligands were docked with the proteins, and all exhibited higher docking score than the standard drug dimethyl fumarate. The TNF- α inhibitors with PDB id such as 2ZJC, 2ZPX and PDE4 Inhibitors with PDB ID such as 3SL3, 1PTW are selected as target proteins, acridone had the best docking score of 19.3502 than standard value 12.997, and with PDB ID 3SL3, acridone showed 26.025 as docking score over the standard value 21.995. it interacted well with the active sites of the proteins. Thus, we infer that these studies will be a leader, in designing new and improved drug target for psoriatic therapy.