Optiverse library

The selections of compounds are made using a variety of methods, such as dissimilarity selection (16), optiverse library selection (17), Jarvis-Park clustering (18), and cell-based methods (19). All these methods attempt to choose a set of compounds that represent the molecular diversity of the available compounds as efficiently as possible. A consequence of this is that only a few compounds around any given molecular scaffold may be present in a HTS screening... 

The design of compounds within each of these paradigms is discussed in the following sections in the context of the Optiverse library,4,5 utilizing a design process developed at Tripos Inc.6 and subsequent synthesis done at MDS Panlabs.7 The process is also similar to that employed in Tripos LeadQuest library and one may infer some similarities to other synthesized libraries involving preselection of reaction products. 

A more comprehensive description of the Optiverse library design process,4,5 discussion of some of the descriptors of chemical structure and properties,8 and the validation methods used to ensure how well the descriptors represented molecular diversity9 appear elsewhere. However, for clarity, some of the relevant factors associated with these are discussed in this section. Note also that explicit discussions of Panlabs experimental chemistry are described elsewhere.10... 

All of these criteria are important to designing a library for lead discovery, and all will be discussed in the following paragraphs and sections in the context of the work carried out to develop the Optiverse and LeadQuest libraries. 

Figure 1. A simplified plot of the distribution of molecules (symbols) in an idealized two-dimensional chemical property space. The upper plot (a) represents a database consisting of discrete sets of close analogues. The lower plot (b) represents the Optiverse library. (Adapted from ref. 4. Copyright 1996 The Society for Biomolecular Screening, Inc.).

Figure 2. A scheme depicting the Optiverse library design for a two-step reaction, where symbols denote generic reagent classification.

Synthesized libraries of compounds such as Optiverse are not the only source of new leads. Natural products also play an important role in lead discovery. There are numerous examples where natural products have led to the discovery of new drugs. It is also clear that they represent an inexpensive source of nature s molecular diversity in a lead discovery program. However, a key limitation that must be overcome if leads are to be developed into drugs is they are usually difficult to synthesize, thereby making it more resource-intensive to generate related compounds with better properties. 

L Taylor, C Garr, M Kobel, L Burton, L Cameron, W McFee. Quality control of the Optiverse library by mass spectrometry. Proceedings of the 45th ASMS Conference on Mass Spectrometry and Allied Topics, Palm Springs, CA, 1997, p. 1248. 

Articles from two companies have reviewed their approaches to solution phase libraries. Merritt et al. [1] described the evolution of approaches at Glaxo Wellcome. The initial approach to pooled libraries was successful in identifying leads for medicinal chemistry programmes but also identified problems and prompted future efforts to be directed to discrete libraries. Garr et al. [2] reviewed the methods used at Panlabs for preparation and analysis of three classes of compounds for the Optiverse Screening Library. A series of solution phase libraries based on 4-aminopiperidine, piperazine and 4-aminobenzylamine were synthesised by acylation, sulphonylation and N-alkylation. 

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