Receptor-based discovery strategies for insecticides and parasiticides: a review.

Drug discovery is an iterative process with high risks and low chance of success. New genomics technologies allow veterinary medicine and agrochemical companies to validate and functionally screen new receptor-based targets, including neuropeptide G-protein coupled receptors, which were previously not amenable to high throughput screening. However this is just the first step in a long process to translate a mechanistic assay hit into a drug on the market. In addition to effectively eradicating pests on crops and parasites on their host, the molecules must also be safe, cheap to synthesise, formulatable and patentable. This is a costly process in which early attrition of unsuitable molecules is key to any successful program. Although first principle discovery is risky the ultimate benefits are considerable and future genomics resources will help to generate higher quality hits to strengthen the discovery pipeline.

[1]  M. J. Gardner,et al.  COMBINATORIAL SYNTHESIS : THE DESIGN OF COMPOUND LIBRARIES AND THEIR APPLICATION TO DRUG DISCOVERY , 1995 .

[2]  T. Kubiak,et al.  Differential Activation of “Social” and “Solitary” Variants of the Caenorhabditis elegans G Protein-coupled Receptor NPR-1 by Its Cognate Ligand AF9* , 2003, Journal of Biological Chemistry.

[3]  Solomon Nwaka,et al.  Innovative lead discovery strategies for tropical diseases , 2006, Nature Reviews Drug Discovery.

[4]  Ricardo Macarrón,et al.  Design and Implementation of High Throughput Screening Assays , 2011, Molecular biotechnology.

[5]  J. Minic,et al.  Yeast system as a screening tool for pharmacological assessment of g protein coupled receptors. , 2005, Current medicinal chemistry.

[6]  F. Hauser,et al.  Identifying neuropeptide and protein hormone receptors in Drosophila melanogaster by exploiting genomic data. , 2006, Briefings in functional genomics & proteomics.

[7]  Magnus W. Walter From serendipity to design - making agrochemicals to order , 2003 .

[8]  B A Kenny,et al.  The application of high-throughput screening to novel lead discovery. , 1998, Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques.

[9]  T. Geary,et al.  Nematode neuropeptide receptors and their development as anthelmintic screens , 2005, Parasitology.

[10]  E. Duzic,et al.  Genetic screens in yeast to identify mammalian nonreceptor modulators of G-protein signaling , 1999, Nature Biotechnology.

[11]  J. Broach,et al.  Functional expression of CXCR4 in Saccharomyces cerevisiae in the development of powerful tools for the pharmacological characterization of CXCR4. , 2006, Methods in molecular biology.

[12]  J. Dow,et al.  Model-organism genomics in veterinary parasite drug-discovery. , 2005, Trends in parasitology.

[13]  W. Janzen,et al.  High-throughput screening: advances in assay technologies. , 1997, Current opinion in chemical biology.

[14]  A. Hopkins,et al.  The druggable genome , 2002, Nature Reviews Drug Discovery.

[15]  Miklos Feher,et al.  Property Distributions: Differences between Drugs, Natural Products, and Molecules from Combinatorial Chemistry , 2003, J. Chem. Inf. Comput. Sci..

[16]  W. Luyten,et al.  Functional characterization of the putative orphan neuropeptide G‐protein coupled receptor C26F1.6 in Caenorhabditis elegans , 2004, FEBS letters.

[17]  Andreas Sewing,et al.  Evaluating Real-Life High-Throughput Screening Data , 2005, Journal of biomolecular screening.

[18]  Shay Bar-Haim,et al.  G protein-coupled receptors: in silico drug discovery in 3D. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[19]  William Thomsen,et al.  Functional assays for screening GPCR targets. , 2005, Current opinion in biotechnology.

[20]  T. Kubiak,et al.  Functional Annotation of the Putative Orphan Caenorhabditis elegans G-protein-coupled Receptor C10C6.2 as a FLP15 Peptide Receptor* , 2003, Journal of Biological Chemistry.

[21]  T. Kubiak,et al.  Type A allatostatins from Drosophila melanogaster and Diplotera puncata activate two Drosophila allatostatin receptors, DAR-1 and DAR-2, expressed in CHO cells. , 2001, Biochemical and biophysical research communications.

[22]  P. Taghert,et al.  Widely distributed Drosophila G-protein-coupled receptor (CG7887) is activated by endogenous tachykinin-related peptides. , 2006, Journal of neurobiology.

[23]  E. Ward,et al.  Target-based discovery of crop protection chemicals , 1999, Nature Biotechnology.

[24]  T. Geary,et al.  Inhibitory effects of nematode FMRFamide-related peptides (FaRPs) on muscle strips fromAscaris suum , 1995, Invertebrate Neuroscience.

[25]  Yael Marantz,et al.  Modeling the 3D structure of GPCRs: advances and application to drug discovery. , 2003, Current opinion in drug discovery & development.

[26]  F. Lombardo,et al.  Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. , 2001, Advanced drug delivery reviews.

[27]  J. Wölcke,et al.  Miniaturized HTS technologies - uHTS. , 2001, Drug discovery today.