Chemoinformatics Research at the University of Sheffield: A History and Citation Analysis

This paper reviews the work of the Chemoinformatics Research Group in the Department of Information Studies at the University of Sheffield, focusing particularly on the work carried out in the period 1985-2002. Four major research areas are discussed, these involving the development of methods for: substructure searching in databases of three-dimensional structures, including both rigid and flexible molecules; the representation and searching of the Markush structures that occur in chemical patents; similarity searching in databases of both two-dimensional and three-dimensional structures; and compound selection and the design of combinatorial libraries. An analysis of citations to 321 publications from the Group shows that it attracted a total of 3725 residual citations during the period 1980-2002. These citations appeared in 411 different journals, and involved 910 different citing organizations from 54 different countries, thus demonstrating the widespread impact of the Group's work

Design, synthesis and biological evaluation of small molecules for controlling cellular development

Cellular differentiation is a process directed by a wide range of controlling signaling molecules and pathways. All-trans-retinoic acid (ATRA) is one such compound that shows a wide range of biological activity. The endogenous effects of ATRA have the potential to be translated into many in vitro and in vivo applications; however, its administration is associated with many drawbacks. Consequently, a large group of synthetic analogues known as synthetic retinoids - that are structurally similar to ATRA have been prepared and tested in vitro in the search for higher stability and more potency. A small library of stable synthetic retinoids known as EC and GZ derivatives were prepared and their biological activity investigated using TERA2.cl.SP12 human embryonal carcinoma (EC) stem cells and SHSY5Y neuroblastoma cells. Two compounds, EC23 and GZ25 were found to inhibit cellular proliferation and induce neural differentiation in both cell lines. EC50s showed higher binding affinity of these two analogues to all RAR types and was confirmed by how they fit into the binding pocket of the different RARs. They bind into the binding pocket through a hydrophilic network of carboxylate group with Arg (salt bridge) and Ser (two hydrogen bonds) residues similar to ATRA. These effects were thoroughly characterized and quantified by monitoring the phenotypic changes of both cell lines and the gene expression markers such as RAR-β, PAX6, NeuroD1 which showed higher order of efficacy for induction of neuronal differentiation.In this study, the combined use of calculated chemical structures, molecular docking tools with receptor binding assays and biological characterization was useful to probe, and hence, understand the biological activity of certain synthetic retinoids with the ultimate goal of designing more specific synthetic retinoic acid derivatives