Search

This paper reports a comparison of calculated molecular properties and of 2D fragment bit-strings when used for the selection of structurally diverse subsets of a file of 44295 compounds. MaxMin dissimilarity-based selection and k-means cluster-based selection are used to select subsets containing between 1% and 20% of the file. Investigation of the numbers of bioactive molecules in the selected subsets suggest: that the MaxMin subsets are noticeably superior to the k-means subsets; that the property-based descriptors are marginally superior to the fragment-based descriptors; and that both approaches are noticeably superior to random selection.

This paper reviews the use of similarity searching in chemical databases. It begins by introducing the concept of similarity searching, differentiating it from the more common substructure searching, and then discusses the current generation of fragment-based measures that are used for searching chemical structure databases. The next sections focus upon two of the principal characteristics of a similarity measure: the coefficient that is used to quantify the degree of structural resemblance between pairs of molecules and the structural representations that are used to characterize molecules that are being compared in a similarity calculation. New types of similarity measure are then compared with current approaches, and examples are given of several applications that are related to similarity searching.

The commercially-available database systems for storing and searching Markush structures from chemical patents have undergone little change since their launch some twenty years ago. However, the past few years have seen the area become an active one again for research and development. This presentation offers an overview and commentary on recent and current activity, and discusses the prospects for improved access to structural information in the patent literature [1]. The existing curated Markush databases remain the gold standard, though several groups, both academic and commercial, continue to work on automatic analysis of full-text patents. This has involved not only the identification of specific-structure nomenclature and its conversion to structure-searchable records, but also the attempted reconstruction of searchable representations of complete Markush structures. The advantages and disadvantages of these approaches, and the prospects for their successful commercial exploitation, are discussed. New commercial software for searching Markush structure databases is being developed by several groups. These employ both conventional substructure search approaches (e.g. ChemAxon, Digital Chemistry), and novel algorithms, in some cases based on various forms of similarity and approximate structure matching (e.g. DecrIPt, IBM). These approaches are summarised and compared, and the opportunity their in-house implementation provides for integration of chemical patent information with the drug-discovery process is discussed. Practitioners have long been aware of the inadequacies and complexities of the existing systems, and the extent to which a new generation of systems may satisfy their requirements is discussed. The possible role of systematic evaluation of retrieval performance (in particular, the TREC-CHEM project) is addressed.

The privatisation and reorganisation of British Telecom (BT) presented its various divisions with the problem of transferring commercial awareness at the top management level to middle management level. A management development programme was designed which combined computer‐based business strategy modelling and “best practice” modelling in human relations. These areas were previously treated separately. The greatest problem for senior managers was modifying their values. For middle managers the problem was that their values were overturned and themselves threatened. The one‐week courses allowed fears and confusions to be aired and examined. By exposing managers to “best practice” procedures they were given frameworks to help them determine how to forge a relationship between a sensible economic strategy and a complementary culture. The programme has been very successful and is to be implemented in other BT businesses.

Mergers, takeovers and changes in products or markets confront managers with major cultural change in their organisations. This article looks specifically at British Telecom, the different demands made on managers pre‐ and post‐privatisation and describes now management development programmes helped managers to change their style.

An association between Graves' disease and the human leukocyte antigen (HLA) system has previously been reported. The disease was more strongly associated with the HLA D locus antigen Dw3 than with HLA B8. Products of the HLA D locus are determined by the interaction of test cells with standard typing lymphocytes, a technically difficult procedure. Recently, it has been possible to type serologically for D locus related (DRw) specificities on peripheral bone marrow-derived (B) lymphocytes. Blood B lymphocytes from 50 unrelated controls and 41 patients with Graves' disease were typed for seven HLA DRw specificities. 28 patients with Graves' disease (68%) were positive for DRw3, in contrast to 14 controls (28%); whereas only 21 patients (50%) were HLA B8 positive, compared with 13 (26%) controls. Thus, positivity for DRw3 afforded a relative risk for Graves' disease of 5.5, whereas that for HLA B8 amounted to 3.0. Additionally, a family with multiple cases of Graves' disease in which the disease was previously shown to be inherited with the haplotype, was linked to DRw2, which suggests that the susceptibility to the disease was inherited in association with that antigen. Two HLA B/glyoxalase recombination events were observed in this family; in both instances HLA DRw followed HLA B. This study thus demonstrates that the disease susceptibility gene for Graves' disease is in strong linkage disequilibrium with DRw3; however, it may be associated with other DRw specificities and inherited within family units in association with them.

Although HLA-B27 carries a high relative risk for development of ankylosing spondylitis (AS), most B27 positive individuals do not have spondylitis. One interpretation of this observation is that there may be 2 types of B27, 1 which carries the risk factor and 1 which does not. If this were the case, then with the help of markers closely linked to HLA-B, it might be possible to detect differences between the B27 haplotypes in AS patients and those in healthy probands. We studied 197 members of 18 families with known AS and 110 members of 19 families in which HLA-B27 was present without any known inflammatory spinal disease. HLA antigens A, B, and C and alleles of complement components C2, C4, and Factor B and glyoxalase-1 were determined in all cases. Detailed haplotypes were assigned and their associations with development of the disease were examined. We were unable to identify any distinct HLA-B27 haplotype associated with AS; 2 common haplotypes and several miscellaneous ones were found in both groups. Thinking that the development of AS might be influenced by the other, non-B27 haplotype, we analyzed this and found that there was no detectable influence. The data do not contradict the notion that B27 in whites is a single entity and is itself the susceptibility factor predisposing to the development of ankylosing spondylitis.

Typing for genetic variation in the second complement component C2 was performed on sera from HLA haplotyped Canadian families. Part of the data has been studied and analysed as a population; in addition there is a further random collection of haplotypes bearing the C2*2 allele. In the population data there were 444 separate haplotypes from unrelated parents or other founders: 4.7% of the haplotypes carried the uncommon allele C2*2; one haplotype carried the rare C2*3. Study of C2 2–1 heterozygotes in the population data revealed 59 haplotypes which carried the common C2*1 allele and one which carried a deficiency allele C2*0. The remaining haplotypes carried either C2* 1 or else an undetectable C2*0 allele. In the entire data there were 281 meioses informative for C2. The only recombinant between HLA-B and C2 showed the C2 locus to be on the DR side of the B locus. Strong allelic association between C2 *2 and Bw22 and less strong association between C2 *2 and B15 suggested the possibility of two ancestral C2 mutants. Examination of other markers on these and subsequently collected haplotypes do not conflict with this idea since the B15 haplotypes mostly carry C4A *4, C4B*2 whilst the Bw22 haplotypes mostly carry C4A*4, C4B*4. The alternative idea, that there was one original mutant which crossed over from a B15 to a Bw22 haplotype or vice versa is not excluded, however. Since approximate equilibrium has been reached between Bw22 and the HLA-A locus alleles on these C2*2 bearing haplotypes, we conclude that this mutation is at least 5000 years old. Other haplotypes carrying C2*2 are assumed to be ancestral recombinants; if this is true, the C2 locus map position between HLA-B and HLA-DR is confirmed. Study of C2 mutation may provide a model for understanding the genetics of some disease susceptibility genes in the HLA region.