Docking Screens of Noncovalent Interaction Motifs of the Human Subtype-D2 Receptor-75 Schizophrenia Antipsychotic Complexes with Physicochemical Appraisal of Antipsychotics.

Chemoinformatics appraisal and molecular docking were employed to investigate 225 complexes of 75 schizophrenia antipsychotics with the dopamine receptor subtypes D2R, D3R, and D4R. Considering the effective noncovalent interactions in the subtype-D2 receptor selectivity of antipsychotics, this study evaluated the possible physicochemical properties of ligands underlying the design of safer and more effective antipsychotics. The pan-assay interference compounds (PAINs) include about 25% of typical antipsychotics and 5% of atypicals. Popular antipsychotics like haloperidol, clozapine, risperidone, and aripiprazole are not PAINs. They have stronger interactions with D2R and D4R, but their interactions with D3R are slightly weaker, which is similar to the behavior of dopamine. In contrast to typical antipsychotics, atypical antipsychotics exhibit more noncovalent interactions with D4R than with D2R. These results suggest that selectivity to D2R and D4R comes from the synergy between hydrophobic and hydrogen-bonding interactions through their concomitant occurrence in the form of a hydrogen-bonding site adorned with hydrophobic contacts in antipsychotic-receptor complexes. All the antipsychotics had more synergic interactions with D2R and D4R in comparison with D3R. The atypical antipsychotics made a good distinction between the subtype D2 receptors with high selectivity to D4R. Among the popular antipsychotics, haloperidol, clozapine, and risperidone have hydrophobic-hydrogen-bonding synergy with D4R, while aripiprazole profits with D2R. The most important residue participating in the synergic interactions was threonine for D2R and cysteine for D4R. This work could be useful in informing and guiding future drug discovery and development studies aimed at receptor-specific antipsychotics.

The barber's pole worm CAP protein superfamily--A basis for fundamental discovery and biotechnology advances.

Parasitic worm proteins that belong to the cysteine-rich secretory proteins, antigen 5 and pathogenesis-related 1 (CAP) superfamily are proposed to play key roles in the infection process and the modulation of immune responses in host animals. However, there is limited information on these proteins for most socio-economically important worms. Here, we review the CAP protein superfamily of Haemonchus contortus (barber's pole worm), a highly significant parasitic roundworm (order Strongylida) of small ruminants. To do this, we mined genome and transcriptomic datasets, predicted and curated full-length amino acid sequences (n=45), undertook systematic phylogenetic analyses of these data and investigated transcription throughout the life cycle of H. contortus. We inferred functions for selected Caenorhabditis elegans orthologs (including vap-1, vap-2, scl-5 and lon-1) based on genetic networking and by integrating data and published information, and were able to infer that a subset of orthologs and their interaction partners play pivotal roles in growth and development via the insulin-like and/or the TGF-beta signalling pathways. The identification of the important and conserved growth regulator LON-1 led us to appraise the three-dimensional structure of this CAP protein by comparative modelling. This model revealed the presence of different topological moieties on the canonical fold of the CAP domain, which coincide with an overall charge separation as indicated by the electrostatic surface potential map. These observations suggest the existence of separate sites for effector binding and receptor interactions, and thus support the proposal that these worm molecules act in similar ways as venoms act as ligands for chemokine receptors or G protein-coupled receptor effectors. In conclusion, this review should guide future molecular studies of these molecules, and could support the development of novel interventions against haemonchosis.

A practical Java tool for small-molecule compound appraisal.

BACKGROUND: The increased use of small-molecule compound screening by new users from a variety of different academic backgrounds calls for adequate software to administer, appraise, analyse and exchange information obtained from screening experiments. While software and spreadsheet solutions exist, there is a need for software that can be easily deployed and is convenient to use. RESULTS: The Java application cApp addresses this need and aids in the handling and storage of information on small-molecule compounds. The software is intended for the appraisal of compounds with respect to their physico-chemical properties, analysis in relation to adherence to likeness rules as well as recognition of pan-assay interference components and cross-linking with identical entries in the PubChem Compound Database. Results are displayed in a tabular form in a graphical interface, but can also be written in an HTML or PDF format. The output of data in ASCII format allows for further processing of data using other suitable programs. Other features include similarity searches against user-provided compound libraries and the PubChem Compound Database, as well as compound clustering based on a MaxMin algorithm. CONCLUSIONS: cApp is a personal database solution for small-molecule compounds which can handle all major chemical formats. Being a standalone software, it has no other dependency than the Java virtual machine and is thus conveniently deployed. It streamlines the analysis of molecules with respect to physico-chemical properties and drug discovery criteria; cApp is distributed under the GNU Affero General Public License version 3 and available from http://www.structuralchemistry.org/pcsb/. To download cApp, users will be asked for their name, institution and email address. A detailed manual can also be downloaded from this site, and online tutorials are available at http://www.structuralchemistry.org/pcsb/capp.php.

Chemical probing suggests redox-regulation of the carbonic anhydrase activity of mycobacterial Rv1284.

UNLABELLED: The mycobacterial enzyme Rv1284 is a member of the ß-carbonic anhydrase family that is considered essential for survival of the pathogen. The active site cavity of this dimeric protein is characterized by an exceptionally small volume and harbours a catalytic zinc ion coordinated by two cysteine and one histidine residue side chains. Using the natural products polycarpine and emodin as chemical probes in crystallographic experiments and stopped-flow enzyme assays, we report that the catalytic activity can be reversibly inhibited by oxidation. Oxidative conditions lead to the removal of one of the active site cysteine residues from the coordination sphere of the catalytic metal ion by engagement in a disulfide bond with another cysteine residue close by. The subsequent loss of the metal ion, which is supported by crystallographic analysis, may thus render the protein catalytically inactive. The oxidative inhibition of Rv1284 can be reversed by exposing the protein to reducing conditions. Because the physical size of the chemical probes used in the present study substantially exceeds the active site volume, we hypothesized that these compounds exert their effects from a surface-bound location and identified Tyr120 as a critical residue for oxidative inactivation. These findings link conditions of oxidative stress to pH homeostasis of the pathogen. Because oxidative stress and acidification are defence mechanisms employed by the innate immune system of the host, we suggest that Rv1284 may be a component of the mycobacterial survival strategy. DATABASE: Atomic coordinates and structure factors have been deposited in the Protein Data Bank under accession numbers 4yf4, 4yf5 and 4yf6.

Flatworms have lost the right open reading frame kinase 3 gene during evolution.

All multicellular organisms studied to date have three right open reading frame kinase genes (designated riok-1, riok-2 and riok-3). Current evidence indicates that riok-1 and riok-2 have essential roles in ribosome biosynthesis, and that the riok-3 gene assists this process. In the present study, we conducted a detailed bioinformatic analysis of the riok gene family in 25 parasitic flatworms (platyhelminths) for which extensive genomic and transcriptomic data sets are available. We found that none of the flatworms studied have a riok-3 gene, which is unprecedented for multicellular organisms. We propose that, unlike in other eukaryotes, the loss of RIOK-3 from flatworms does not result in an evolutionary disadvantage due to the unique biology and physiology of this phylum. We show that the loss of RIOK-3 coincides with a loss of particular proteins associated with essential cellular pathways linked to cell growth and apoptosis. These findings indicate multiple, key regulatory functions of RIOK-3 in other metazoan species. Taking advantage of a known partial crystal structure of human RIOK-1, molecular modelling revealed variability in nucleotide binding sites between flatworm and human RIOK proteins.

Complexation of thallium(I) with adenosine 5'-monophosphate in aqueous methanol solutions.

The formation constants of the species formed in the systems H+ + thallium(I) + AMP and H+ + AMP have been determined in aqueous solutions of methanol at 25 degrees C and constant ionic strength 0.1 mol dm(-3) sodium perchlorate, using spectrophotometric and potentiometric techniques. Thallium(I) forms two mononuclear 1:1 complexes with AMP of the type TlHL and TlL- in the pH range of study (1-11), where L2- represents the fully dissociated ligand. The formation constants in various media were analyzed in terms of Kamlet and Taft's parameters. Single-parameter correlation of the formation constants, beta111, and beta101, versus alpha (hydrogen-bond donor acidity), beta (hydrogen-bond accepter basicity), and for pi* (dipolarity/polarizability) are relatively poor in all solutions, but multi-parameter correlation represents significant improvement with regard to the single-parameter models. Finally, the results are discussed in terms of the effect of the solvent on complexation.