Computer-aided design of selective COX2 inhibitors: molecular docking of structurally diverse cyclooxygenase-2 inhibitors using FlexX

Motivation: Three-dimensional structures of pharmacologically important macromolecules offer a route to the discovery of new drugs. Understanding the macromolecule-ligand interactions and validation of method used for docking and virtual screening of chemical databases is crucial step in structure-based design. We therefore carried out molecular docking for a set of eighty two structurally diverse COX-1/COX-2 inhibitors including traditional NSAIDs and the recent developed coxibs using FlexX method to find out how good this method differentiate between the active and inactive compounds. Method: FlexX is one of the fast flexible docking method that uses an incremental construction algorithm to place ligands into an active site. The scoring function (empirical binding free energy) of the flexX used to estimate the free binding energy of the protein-ligand complex is called F_score. Results: Reproducibility of the experimental conformations of the bound ligands such as SC-558, indomethacin, flurbiprofen indicates the better performance of FlexX method. Good correlation between the standard FlexX score (F_score) and the COX-2 inhibitory activity (pIC50) was observed. Simple linear regression analysis provided the correlation coefficient values of 0.731 and 0.670 for two classes of COX-2 inhibitors. Conclusions: Flexible docking of eighty two structurally diverse COX-2 inhibitors have been successfully carried out. Some false positives and false negatives were observed but considering the limitations of the available docking programs, the results are encouraging. The detailed analysis of the resulted COX-2-ligand complexes may improve our knowledge in understanding the binding interactions in detail. Thus, this study will be useful for the design of novel COX-2 inhibitors based on docking and the resulted bioactive conformations of the ligands will be useful in building structure-based 3-D QSAR model

Acetaminophen toxicity and resistance in the yeast Saccharomyces cerevisiae

Acetaminophen (paracetamol), one of the most widely used analgesics, is toxic under conditions of overdose or in certain disease conditions, but the mechanism of acetaminophen toxicity is still not entirely understood. To obtain fresh insights into acetaminophen toxicity, this phenomenon was investigated in yeast. Acetaminophen was found to be toxic to yeast cells, with erg mutants displaying hypersensitivity. Yeast cells grown in the presence of acetaminophen were found to accumulate intracellular acetaminophen, but no metabolic products of acetaminophen could be detected in these extracts. The toxicity response did not lead to an oxidative stress response, although it did involve Yap1p. The cytochrome P450 enzymes of yeast, Erg5p and Erg11p, did not appear to participate in this process, unlike the mammalian systems. Furthermore, we could not establish a central role for glutathione depletion or the cellular glutathione redox status in acetaminophen toxicity, suggesting differences from mammalian systems in the pathways causing toxicity. Investigations of the resistance mechanisms revealed that deletion of the glutathione-conjugate pumps Ycf1p (a target of Yap1p) and Bpt1p, surprisingly, led to acetaminophen resistance, while overexpression of the multidrug resistance pumps Snq2p and Flr1p (also targets of Yap1p) led to acetaminophen resistance. The Yap1p-dependent resistance to acetaminophen required a functional Pdr1p or Pdr3p protein, but not a functional Yrr1p. In contrast, resistance mediated by Pdr1p/Pdr3p did not require a functional Yap1p, and revealed a distinct hierarchy in the resistance to acetaminophen

Magnesium bistrifluoromethanesulfonimide as a new and efficient acylation catalyst

Magnesium bistrifluoromethanesulfonimide catalyzed the acetylation of phenols, alcohols, and thiols under solvent-free conditions at room temperature and in short times. Electron-deficient and sterically hindered phenols provided excellent yields. The catalyst was found to be general for acylation with other anhydrides, such as propionic, isobutyric, pivalic, chloroacetic, and benzoic anhydrides. The rate of acylation was influenced by the electronic and steric factors associated with the anhydride. The reaction with less electrophilic anhydrides (e.g., chloroacetic and benzoic anhydrides) required higher temperature (∼80 °C). Chemoselective acetylation, pivalation, and benzoylation took place with acid-sensitive alcohols without any competitive dehydration/rearrangement

One-pot synthesis of nitriles from aldehydes under microwave irradiation: influence of the medium and mode of microwave irradiation on product formation

Chemoselective transformation of aldehyde to nitrile takes place in a one-pot reaction by treatment with H<SUB>2</SUB>NOHHCl in N-methyl-2-pyrrolidinone (NMP) under microwave irradiation using convection mode

Zinc perchlorate hexahydrate as a new and highly efficient catalyst for synthesis of 2-hydroxysulfides by opening of epoxide rings with thiols under solvent-free conditions: application for synthesis of the key intermediate of diltiazem

Commercially available zinc perchlorate hexahydrate [Zn(ClO<SUB>4</SUB>)<SUB>2</SUB>·6H<SUB>2</SUB>O] was found to be highly effective catalyst for opening of epoxide ring by thiols under solvent-free condition at room temperature for efficient synthesis of 2-hydroxysulfides. The catalytic activity of various group I/II metal perchlorates followed the order Zn(ClO<SUB>4</SUB>)<SUB>2</SUB>·6H<SUB>2</SUB>O ≫ Mg(ClO<SUB>4</SUB>)2·6H<SUB>2</SUB>O > Ba(ClO<SUB>4</SUB>)<SUB>2</SUB>·6H<SUB>2</SUB>O ⋙ LiClO<SUB>4</SUB>. The Zn(ClO<SUB>4</SUB>)<SUB>2</SUB>·6H<SUB>2</SUB>O-catalysed reaction of epoxides derived from cyclic and acyclic olefines with thiols afforded β-hydroxysulfides in high yields. Reaction with cycloalkene oxides led to stereoselective formation of the trans-2-hydroxysulfides. Excellent regioselectivity was observed for unsymmetrical epoxides. In case of styrene oxide, the hydroxysulfide from nucleophilic attack at the benzylic carbon of the epoxide was the major product. Preferential nucleophilic attack by thiophenol took place at sterically less hindered position of the epoxide ring of unsymmetrical non-styrenoid alkene oxides. Epichlorohydrin exemplified a case of chemo- and regioselective reaction with no detectable (GC–MS) side product formation by direct displacement of the chlorine atom. The methodology was extended for an efficient synthesis of the key intermediate of diltiazem

Zirconium(IV) compounds as efficient catalysts for synthesis of &#945;-aminophosphonates

Zirconium(IV) compounds are reported as excellent catalysts for a three-component one-pot reaction of an amine, an aldehyde or a ketone, and a di/trialkyl/aryl phosphite to form &#945;-aminophosphonates under solvent-free conditions at rt. Among the various zirconium compounds, ZrOCl<SUB>2</SUB>·8H<SUB>2</SUB>O and ZrO(ClO<SUB>4</SUB>)<SUB>2</SUB>·6H<SUB>2</SUB>O were most effective. The reactions were faster with dialkyl/diaryl phosphites than with trialkyl/triaryl phosphites. No O−Me cleavage occurs with aryl methyl ether and methyl ester groups. &#945;,&#946;-Unsaturated carbonyl moiety does not undergo conjugate addition with the phorphorous moiety

Fluoroboric acid adsorbed on silica gel as a new and efficient catalyst for acylation of phenols, thiols, alcohols, and amines

Fluoroboric acid supported on silica gel efficiently catalyzes acylation of structurally diverse phenols, alcohols, thiols, and amines under solvent free conditions. Acid-sensitive alcohols are smoothly acylated without competitive side reactions

Aqueous mediated heterogeneous catalysis/ edited by Asit K. Chakraborti and Bubun Banerjee.

1 online resourc

Copper(II) tetrafluoroborate-catalyzed acetylation of phenols, thiols, alcohols, and amines

Copper(II) tetrafluoroborate efficiently catalyzes acetyl­ation of structurally diverse phenols, alcohols, thiols, and amines with stoichiometric amounts of Ac<SUB>2</SUB>O under solvent-free conditions at room temperature. Acid-sensitive alcohols are smoothly acetylated without competitive side reactions. The reaction is influenced by the steric and electronic factors associated with the substrate as well as the anhydride. Acetylation of a sterically hindered substrate requires excess of anhydride and longer time. Acylation with less electrophilic anhydrides affords poor to moderate yields