A new lead for nonpeptidic active-site-directed inhibitors of the severe acute respiratory syndrome coronavirus main protease discovered by a combination of screening and docking methods.

The coronavirus main protease, Mpro, is considered to be a major target for drugs suitable for combating coronavirus infections including severe acute respiratory syndrome (SARS). An HPLC-based screening of electrophilic compounds that was performed to identify potential Mpro inhibitors revealed etacrynic acid tert-butylamide (6a) as an effective nonpeptidic inhibitor. Docking studies suggested a binding mode in which the phenyl ring acts as a spacer bridging the inhibitor's activated double bond and its hydrophobic tert-butyl moiety. The latter is supposed to fit into the S4 pocket of the target protease. Furthermore, these studies revealed etacrynic acid amide (6b) as a promising lead for nonpeptidic active-site-directed Mpro inhibitors. In a fluorimetric enzyme assay using a novel fluorescence resonance energy transfer (FRET) pair labeled substrate, compound 6b showed a Ki value of 35.3 M. Since the novel lead compound does not target the S1', S1, and S2 subsites of the enzyme's substrate-binding pockets, there is room for improvement that underlines the lead character of compound 6b.

Screening of electrophilic compounds yields an aziridinyl peptide as new active-site directed SARS-CoV main protease inhibitor.

The coronavirus main protease, Mpro, is considered a major target for drugs suitable to combat coronavirus infections including the severe acute respiratory syndrome (SARS). In this study, comprehensive HPLC- and FRET-substrate-based screenings of various electrophilic compounds were performed to identify potential Mpro inhibitors. The data revealed that the coronaviral main protease is inhibited by aziridine- and oxirane-2-carboxylates. Among the trans-configured aziridine-2,3-dicarboxylates the Gly-Gly-containing peptide 2c was found to be the most potent inhibitor.

Changes in the attitudes of GPs to health screening of patients with learning disabilities

GP's appear reluctant to undertake health screening for people with learning disabilities. This article describes a specialist health screening service delivered mainly by community learning disability nurses to nearly 600 children and adults. Prior to the service being established, 141 GPs within a defined area were surveyed and 51% responded. Although a majority thought the service would be helpful, three-quarters felt it was better provided within the context of specialist services. After screening, 54% of the sample (318 persons) were referred to their GP for further assessment and treatment, nearly all for physoical health needs. A second study investigated the attitudes of 91 GPs who had patients refrrered. Those (45) who reported dealing with a referral were more favourably disposed to undertaking health screening within their practice, whereas those (23) who had been uninvolved continued to opt for specialist provision. Options for encouraging more GPs' to offer preventive health care to theisclient group are discussed, including medical training, extra consulting time and linking community learning disbaility nurses with GP practices.

Development of an ELISA screening test for nitroimidazoles in egg and chicken muscle

An antibody was generated that can bind metronidazole (MNZ), a nitroimidazole drug used in veterinary medicine to treat poultry for coccidiosis and histomoniasis. A direct competitive enzyme-linked immunosorbent assay (cELISA) is described. It was used to characterise binding of this antibody to a number of nitroimidazole drugs. It displayed cross-reactivity with dimetridazole (DMZ), ronidazole (RNZ), hydroxydimetridazole (DMZOH), and ipronidazole (IPZ).

Screening for the coccidiostats halofuginone and nicarbazin in egg and chicken muscle: development of an ELISA

Nicarbazin and halofuginone have been widely used as coccidiostats for the prevention and treatment of coccidiosis in poultry. It has been shown that accidental cross-contamination of feed can lead to residues of these compounds in eggs and/or muscle. This paper describes a direct competitive assay for detecting halofuginone and nicarbazin, developed as qualitative screening assay. In an optimized competitive ELISA, antibodies showed 50% binding inhibition at approximately 0.08 ng ml(-1) for halofuginone and 2.5 ng ml(-1) for dinitrocarbanilide (marker residue for nicarbazin). Extraction from the matrix was carried out with acetonitrile followed by a wash with hexane. The assay's detection capability (CCbeta) for halofuginone was

Screening tablets for DOB using surface-enhanced Raman spectroscopy

2,5,-Dimethoxy-4-bromoamphetamine (DOB) is of particular interest among the various

Evidence of Short-Range Screening in Shock-Compressed Aluminum Plasma

We have investigated the angular variation in elastic x-ray scattering from a dense, laser-shock-compressed aluminum foil. A comparison of the experiment with simulations using an embedded atom potential in a molecular dynamics simulation shows a significantly better agreement than simulations based on an unscreened one-component plasma model. These data illustrate, experimentally, the importance of screening for the dense plasma static structure factor.

Discovery of novel cathepsin S inhibitors by pharmacophore-based virtual high-throughput screening

The cysteine protease cathepsin S (CatS) is involved in the pathogenesis of autoimmune disorders, atherosclerosis, and obesity. Therefore, it represents a promising pharmacological target for drug development. We generated ligand-based and structure-based pharmacophore models for noncovalent and covalent CatS inhibitors to perform virtual high-throughput screening of chemical databases in order to discover novel scaffolds for CatS inhibitors. An in vitro evaluation of the resulting 15 structures revealed seven CatS inhibitors with kinetic constants in the low micromolar range. These compounds can be subjected to further chemical modifications to obtain drugs for the treatment of autoimmune disorders and atherosclerosis.