Binding Conformation of 2-Oxoamide Inhibitors to Group IVA Cytosolic Phospholipase A2 Determined by Molecular Docking Combined with Molecular Dynamics

The group IVA cytosolic phospholipase A2 (GIVA cPLA2) plays a central role in inflammation. Long chain 2-oxoamides constitute a class of potent GIVA cPLA2 inhibitors that exhibit potent in vivo anti-inflammatory and analgesic activity. We have now gained insight into the binding of 2-oxoamide inhibitors in the GIVA cPLA2 active site through a combination of molecular docking calculations and molecular dynamics simulations. Recently, the location of the 2-oxoamide inhibitor AX007 within the active site of the GIVA cPLA2 was determined using a combination of deuterium exchange mass spectrometry followed by molecular dynamics simulations. After the optimization of the AX007-GIVA cPLA2 complex using the docking algorithm Surflex-Dock, a series of additional 2-oxoamide inhibitors have been docked in the enzyme active site. The calculated binding affinity presents a good statistical correlation with the experimental inhibitory activity (r 2 = 0.76, N = 11). A molecular dynamics simulation of the docking complex of the most active compound has revealed persistent interactions of the inhibitor with the enzyme active site and proves the stability of the docking complex and the validity of the binding suggested by the docking calculations. The combination of molecular docking calculations and molecular dynamics simulations is useful in defining the binding of small-molecule inhibitors and provides a valuable tool for the design of new compounds with improved inhibitory activity against GIVA cPLA2

Copper(I)/(II) or silver(I) ions towards 2-mercaptopyrimidine: An exploration of a chemical variability with possible biological implication

Direct reaction of copper(I) chloride with 2-mercaptopyrimidine (pmtH) in the presence of the triphenylphosphine (tpp) in 1:1:2 M ratio forms the mixed ligand Cu(I) complex with formula [CuCl(tpp)2(pmtH)] (1). The dimeric {[Cu(tpp)(pmt)]2 0.5(MeOH)} (2) complex was derived from the reaction of 1 with twofold molar amount of sodium hydroxide. However, the reaction of copper(II) sulfate or nitrate with pmtH and tpp in 1:2:2 M ratio, unexpectedly results in the formation of the [CuSH(tpp)2(pmtH)] (3) complex. Further studies have shown that the [Cu(tpp)2(pmt)] (4) complex is formed by reacting copper(II) acetate with pmtH in the presence of tpp in 1:2:2 M ratio, while in the absent of tpp, the Cu(CH3COO)2 or CuSO4 is found to oxidizes pmtH to its corresponding disulfide (pmt)2. For comparison the mixed ligand silver(I) chloride or nitrate complexes with formula [AgCl(tpp)2(pmtH)] (5) or [Ag(NO3)(tpp)2(pmtH)] (6) are also synthesized by reacting of the AgCl or AgNO3 with pmtH and tpp in 1:2:2 M ratio. The complexes have been characterized by elemental analyses, m.p., vibrational spectroscopy (mid-, far-FT-IR and Raman), 1 H NMR, UV–Vis, ESI-MS, TG–DTA spectroscopic techniques and single crystal X-ray crystallography at ambient conditions. Photolysis of 1–6, was also studied and the results showed formation of triphenylphosphine oxide. The complexes 1–6, were used to study their influence upon the catalytic peroxidation of the linoleic acid by the enzyme lipoxygenase (LOX) experimentally and theoretically. The binding of 1–4 with LOX was also investigated by saturation transfer difference 1 H NMR experiments (STD

Mono- and Binuclear Copper(I) Complexes of Thionucleotide Analogues and Their Catalytic Activity on the Synthesis of Dihydrofurans

The reaction of copper­(I) halides with 2-thiouracil (TUC), 6-methyl-2-thiouacil (MTUC), and 4-methyl-2-mercaptopyrimidine (MPMTH) in the presence of triphenylphosphine (tpp) in a 1:1:2 molar ratio results in a mixed-ligand copper­(I) complex with the formulas [Cu₂(tpp)₄(TUC)­Cl] (<b>1</b>), [Cu₂(tpp)₄(MTUC)­Cl] (<b>2</b>), [Cu­(tpp)₂(MPMTH)­Cl]·¹/₂CH₃OH (<b>3</b>), [Cu­(tpp)₂(MTUC)­Br] (<b>4</b>), and [Cu­(tpp)₂(MTUC)­I]·¹/₂CH₃CN (<b>5</b>). The complexes have been characterized by FT-IR, ¹H NMR, and UV–vis spectroscopic techniques and single-crystal X-ray crystallography. Complexes <b>1</b> and <b>2</b> are binuclear copper­(I) complexes. Two phosphorus atoms from tpp ligands are coordinated to the copper­(I) ions, forming two units that are linked to each other by a deprotonated TUC or MTUC chelating ligand through a sulfur bridge. A linear Cu–S–Cu moiety is formed. The tetrahedral geometry around the metal centers is completed by the nitrogen-donor atom from the TUC or MTUC ligand for the one unit, while for the other one, it is completed by the chloride anion. Two phosphorus atoms from two tpp ligands, one sulfur atom from MPMTH or MTUC ligand, and one halide anion (Cl, Br, and I) form a tetrahedron around the copper ion in <b>3</b>–<b>5</b> and two polymorphic forms of <b>4</b> (<b>4a</b> and <b>4b</b>). In all of the complexes, either mono- or binuclear intramolecular O–H···X hydrogen bonds enhance the stability of the structures. On the other hand, in almost all cases of mononuclear complexes (with the exception of a symmetry-independent molecule in <b>4a</b>), intermolecular NH···O hydrogen-bonding interactions lead to dimerization. Complexes <b>1</b>–<b>5</b> were studied for their catalytic activity for the intermolecular cycloaddition of iodonium ylides toward dihydrofuran formation by HPLC, ¹H NMR, and LC-HRMS spectroscopic techniques. The results show that the geometry and halogen and ligand types have a strong effect on the catalytic properties of the complexes. The highest yield of dihydrofurans was obtained when “linear” complexes <b>1</b> and <b>2</b> were used as the catalysts. The activity of the metal complexes on the copper­(I)-catalyzed and uncatalyzed intramolecular cycloaddition of iodonium ylide is rationalized through electronic structure calculation methods, and the results are compared with the experimental ones