Applications of combinatorial chemistry to drug design and development.

This article is a subjective review of the literature from 1998 to April 1999 describing combinatorial chemistry as applied to drug discovery. The first two sections cover proteinase inhibition and small molecule lead discovery for other target classes. The final section describes those combinatorial chemistry-related technologies we think most likely to impact on drug discovery in the future.

Comparison of algorithms for dissimilarity-based compound selection.

Dissimilarity-based compound selection has been suggested as an effective method for selecting structurally diverse subsets of chemical databases. This article reports a comparison of several maximum-dissimilarity and sphere-exclusion algorithms for dissimilarity-based selection. The effectiveness of the algorithms is quantified by the numbers of biological activity classes identified in subsets selected from the World Drugs Index database, and by the numbers of active compounds identified in feedback searches of this database. The experiments demonstrate the general effectiveness and efficiency of the MaxMin algorithm.

Parallel-compound synthesis: methodology for accelerating drug discovery.

Parallel compound synthesis enables large numbers of individual compounds to be prepared simultaneously using semiautomated techniques. This fast and efficient methodology has an important role to play in accelerating lead optimisation and hence the whole drug discovery process. The potential of this strategy to rapidly optimise chemical leads and provide structure-activity relationship (SAR) information was demonstrated in two therapeutic areas, antiviral agents (herpes simplex virus), and neurokinin-2 receptor antagonists.

Computational approaches in the post-genomic era - how will we cope?

The Discussion Forum provides a medium for airing your views on any issues related to the pharmaceutical industry and obtaining feedback and discussion on these views from others in the field. You can discuss issues that get you hot under the collar, practical problems at the bench, recently published literature, or just something bizarre or humorous that you wish to share. Publication of letters in this section is subject to editorial discretion and company-promotional letters will be rejected immediately. Furthermore, the views provided are those of the authors and are not intended to represent the views of the companies they work for. Moreover, these views do not reflect those of Elsevier, Drug Discovery Today or its editorial team. Please submit all letters to Rebecca Lawrence, News & Features Editor, Drug Discovery Today, e-mail: Rebecca.Lawrence@current-trends.com

The application of non-combinatorial chemistry to lead discovery.

Non-combinatorial chemistry is a powerful technology for the synthesis of large numbers of compounds, with complete control over the properties of those compounds. We have developed a Library Creation, Registration and Automation system (LiCRA), which harnesses an efficient non-combinatorial chemistry design and synthesis engine, together with high-throughput automated purification. This LiCRA system also operates in a closed loop mode for hit-to-lead optimization, and contains an integrated IT system that controls and facilitates all aspects of the operation from design to registration. Quality has been our watchword, from the quality of compound design through to the quality of the products.

UK-69,578, a novel inhibitor of EC 3.4.24.11 which increases endogenous ANF levels and is natriuretic and diuretic.

A search for potent inhibitors of EC 3.4.24.11, an enzyme which is found most abundantly in the kidney and which degrades atrial natriuretic factor, has led to the identification of UK-69,578. Structure-activity studies starting from substituted N-carboxymethyl dipeptide inhibitors resulted in the introduction of a cyclo-alkane P1' residue and in the replacement of the aza-link between P1 and P1' residues by a methylene group, with a net ten-fold potency gain. UK-69,578 increases endogenous ANF levels and produces natriuretic and diuretic responses intravenously in mice.