Libraries computer-assisted

Grassy, G., Yasri, A., Sans, P., Armbruster, A. M., Lahana, R. and Fauchere, J. L. (1997) Molecular dynamics simulations as a tool to investigate the three-dimensional diversity of peptide and pseudopeptide libraries. In Computer-assisted lead finding and optimization. Current tools for medicinal chemistry, Van de Waterbeemd, H., Testa, B., and Folkers, G. (eds.), Wiley-VCH, Basel, pp. 209-222. 

An example of a leading chemical CRO is Albany Molecular (AMRI). It had chemistry revenues 184 million in 2005. AMRI does organic synthesis and chemistry development, supported by computational chemistry for molecular modeling, with computer-assisted drug design. Furthermore, it offers different types of libraries custom, semiexclusive, focused, and natural products. Finally, AMRI conducts its own proprietary R D aimed at licensing preclinical and clinical compounds. 

The conventional approach is to extract from the TIC profile the mass spectra of all peaks above a predetermined intensity and to perform either manual or computer-assisted [39] identification of each mass spectrum. Analysis of mass spectra should be carried out only by properly trained technologists, under the supervision of a qualified laboratory director. Libraries of mass spectra should be available for identification of peaks that are not readily recognized. This library should be user-created, indexed by retention time and molecular weight, and have the capacity to be expanded and edited. 

They generally lack sensitivity and a direct relation to molecular structure. GC-MS is fast, direct, and very sensitive, and the spectrum provides a result which puts identification beyond dispute. Computer-assisted systems are now available which embody extensive drug reference libraries and can be automatically searched to identify unknown spectra. The further development of chemical ionization and mass fragmentography methods using stable isotopes now permits very accurate quantitative work. 

Xeptagen S.p.A. has improved a computer assisted combinatorial chemistry approach, based on an innovative application of Mitsunobu reaction, that could be used to design and synthesize new peptido-mimetic libraries, in order to find novel leads efficient in different biological targets (Figure 3.10). 

In collaboration with University of Trieste, we have developed rational approaches for the design and synthesis of peptidomimetic and non-peptidic inhibitors of HIV PR, utilizing structure-based [12-15], as well as combinatorial, library design methods [16, 17]. In this paper, we survey computer-assisted studies on the design, focusing and in silico screening of virtual combinatorial libraries of peptidomimetics and cyclic ureas, as potential anti-HIV agents, that were carried out in our laboratory. 

We summarize here the efforts to generate a virtual library of peptidomimetic pentameric inhibitors of the HIV PR, derived from ritonavir (Figure 4.1), developed by the Abbott Laboratories [18,19] using computer-assisted combinatorial chemistry methods [20]. 

Topics include the generation of molecular diversity by chemical methods using solution- and solid-phase chemistries, biological approaches for the production and screening of peptides, antibody and oligonucleotide libraries, and the application of computer-assisted approaches to guide library synthesis. 

The basic ILLINET Online Network (Illinois Online Network) was used as the major computer-assisted information retrieval program. Within this network IBIS (Illinois Bibliographic Information Service), which provides abstracts taken from journal articles published from 1991 through December 1993, and CARL UnCover (Colorado Alliance of Research Libraries), which provides titles to journal articles published in 1988 through December 1993, afforded much of the current and recent information reported on here. Abstracts of the pertinent literature published from 1982 through mid-1993 were also obtained directly from CA (Chemical Abstracts). It is hoped that the overlap provided this way assures the broadest retrieval of published results. All of these sources were searched by means of the following key words ... 

Lundstedt, T., Andersson, P.M., Clementi, S., Cruciani, G., Kettaneh, N., Linusson, A., Norden, B., Pastor, M., Sjostrom, M. and Wold, S. Intelligent Combinatorial Libraries. In Computer-Assisted Lead Finding and Optimization Ed. H. van de Waterbeemd, Verlag Helvetica Chimica Acta. Basel, Switzerland, 1997, 191-208. 

Several reviews dealing with different areas of library design have been published (149-159) their content and the references cited therein should further illustrate the future tendencies of computer-assisted combinatorial chemistry. 

A new lipase assay has been developed and used to screen the Aventis compound library. Several classes of hits have been elucidated - one of which, the oxadiazo-lones, has been selected for a chemical optimization program. Computer-assisted experimental design has enabled optimization wifh respect to activity and selectivity. Small potent inhibitors were obtained that are drug-like and follow fhe Li-pinsky rules of five, which are often useful for a first theoretical prediction of oral bioavailability [54]. Ongoing pharmacological trials will show if lipase inhibitors can successfully treat diabetes and afherosclerosis. 

The fundamental strategy of computer-assisted library design is shown in Fig. 1. The set-up of the reaction scheme and building block selection lead to the virtual combinatorial library. Due to the virtual character of this library its size is not limited by experimental restrictions, and depends mainly on the number of available building blocks. 

Fig. 1 Computer-assisted design strategy. At best, building blocks are selected by optimizing the enumerated virtual library (product-based selection).

A brief introduction into the computer-assisted design strategy is given in Section 9.2. Basic theory and methods applied to the different steps of library design are described in the following sections in more detail ... 

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