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

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

Revealing the astragalin mode of anticandidal action.

Due to limited arsenal of systemically available antifungal agents, infections caused by Candida albicans are difficult to treat and the emergence of drug-resistant strains present a major challenge to the clinicians worldwide. Hence further exploration of potential novel and effective antifungal drugs is required. In this study we have explored the potential of a flavonoid, astragalin, in controlling the growth of C. albicans, in both planktonic and biofilm forms by microdilution method; and in regulating the morphological switch between yeast and hyphal growth. Astragalin ability to interfere with membrane integrity, ergosterol synthesis and its role in the regulation of genes encoding for efflux pumps has been addressed. In our study, astragalin treatment produced good antimicrobial and significant antibiofilm activity. Anticandidal activity of astragalin was not related to ERG11 downregulation, neither to direct binding to CYP51 enzyme nor was linked to membrane ergosterol assembly. Instead, astragalin treatment resulted in reduced expression of CDR1 and also affected cell membrane integrity without causing cytotoxic effect on human gingival fibroblast cells. Considering that astragalin-mediated decreased expression of efflux pumps increases the concentration of antifungal drug inside the fungal cells, a combinatorial treatment with this agent could be explored as a novel therapeutic option for candidiasis

Conformational Analysis of [Phe91]ΜΒΡ83-99 and [Tyr91]ΜΒΡ83-99 peptide analogues and study of their interactions with HLA-DR2 receptor and human TCR receptors using Molecular Dynamics

The two new synthetic analogues of the MBP83–99 epitope substituted at Lys91 (primary TCR contact) with Phe [MBP83–99 (Phe91)] or Tyr [MBP83–99 (Tyr91)], have been structurally elucidated using 1D and 2D high resolution NMR studies. The conformational analysis of the two altered peptide ligands (APLs) has been performed and showed that they adopt a linear and extended conformation which is in agreement with the structural requirements of the peptides that interact with the HLA-DR2 and TCR receptors. In addition, Molecular Dynamics (MD) simulations of the two analogues in complex with HLA-DR2 (DRA, DRB1*1501) and TCR were performed. Similarities and differences of the binding motif of the two analogues were observed which provide a possible explanation of their biological activity. Their differences in the binding mode in comparison with the MBP83–99 epitope may also explain their antagonistic versus agonistic activity. The obtained results clearly indicate that substitutions in crucial amino acids (TCR contacts) in combination with the specific conformational characteristics of the MBP83–99 immunodominant epitope lead to an alteration of their biological activity. These results make the rational drug design intriguing since the biological activity is very sensitive to the substitution and conformation of the mutated MBP epitopes

Strategies in the rational drug design

Rational design is applied in the discovery of novel lead drugs. Its rapid development is mainly attributed to the tremendous advancements in the computer science, statistics, molecular biology, biophysics, biochemistry, medicinal chemistry, pharmacokinetics and pharmacodynamics experienced in the last few decades. The promising feature that characterizes the application of rational drug design is that it uses for developing potential leads in drug discovery all known theoretical and experimental knowledge of the system under study. The utilization of the knowledge of the molecular basis of the system ultimately aims to reduce human power cost, time saving and laboratory expenses in the drug discovery. In this review paper various strategies applied for systems which include: (i) absence of knowledge of the receptor active site; (ii) the knowledge of a homology model of a receptor, (iii) the knowledge of the experimentally determined (i.e. X-ray crystallography, NMR spectroscopy) coordinates of the active site of the protein in absence and (iv) the presence of the ligand will be analyzed

The use of J-coupling as a sole criterion to assign the total absolute stereochemistry of new pyrrolidinone class synthetic analogs, derived from S-pyroglutamic acid

During the synthesis of new pyrrolidinone analogs possessing biological activity it is intriguing to assign their absolute stereochemistry as it is well known that drug potency is influenced by the stereochemistry. The combination of J-coupling information with theoretical results was used in order to establish their total stereochemistry when the chiral center of the starting material has known absolute stereochemistry. The J-coupling can be used as a sole criterion for novel synthetic analogs to identify the right stereochemistry. This approach is extremely useful especially in the case of analogs whose 2D NOESY spectra cannot provide this information. Few synthetic examples are given to prove the significance of this approach. © 2016 Elsevier B.V