Current Opinion in Chemical Biology

Blood-brain barrier permeability considerations for CNS-targeted compound library design.

Publication Date: 2008 Apr 21 PMID: 18435937
Authors: Hitchcock, S. A.
Journal: Curr Opin Chem Biol

A further refinement of the concept of drug-likeness is required for compound libraries intended for central nervous system (CNS) targets to account for the limitations imposed by blood-brain barrier permeability. This review describes criteria and processes that can be applied in the de novo design and assembly of libraries to increase the odds of compounds residing within CNS-accessible chemical space. A number of published examples where CNS activity and/or penetration characteristics have been a factor in library design are discussed.

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Increasing carbohydrate diversity via amine oxidation: aminosugar, hydroxyaminosugar, nitrososugar, and nitrosugar biosynthesis in bacteria.

Publication Date: 2008 Apr 18 PMID: 18424273
Authors: Timmons, S. C. - Thorson, J. S.
Journal: Curr Opin Chem Biol

Bacterial secondary metabolites often contain carbohydrate attachments that play a significant role in conferring biological activity. A small proportion of these bioactive sugars are derived from aminosugar oxidation to ultimately provide hydroxyaminosugars, nitrososugars, and nitrosugars. Recent advances in the elucidation of hydroxyaminosugar-, nitrososugar-, and nitrosugar-containing natural product gene clusters have enabled the proposal of biosynthetic pathways, the in vitro characterization of aminosugar oxidases, and the structure determination of key enzymes. This article focuses upon the key enzymatic transformations in aminosugar, hydroxyaminosugar, nitrososugar, and nitrosugar biosynthesis, as well as the unique chemical reactivity of alkoxyaminosugars, with a particular focus upon developments within the past two years.

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Coverage and bias in chemical library design.

Publication Date: 2008 May 2 PMID: 18423416
Authors: Gregori-Puigjane, E. - Mestres, J.
Journal: Curr Opin Chem Biol

The design of chemical libraries directed to target classes is an activity that requires the availability of ligand pharmacological data and/or protein structural data. On the basis of the knowledge derived from these data, chemical libraries directed mainly to G protein-coupled receptors, kinases, proteases, and nuclear receptors have been assembled. However, current design strategies widely overlook assessing the potential ability of the compounds contained in a focused library to provide uniform ample coverage of the protein family they intend to target. Here, we discuss the use of in silico target profiling methods as a means to estimate the actual scope of chemical libraries to probe entire protein families and illustrate its applicability in optimizing the composition of compound sets to achieve maximum coverage of the family with minimum bias to particular targets.

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Dissimilarity-based approaches to compound acquisition.

Publication Date: 2008 May 7 PMID: 18423415
Authors: Lajiness, M. - Watson, I.
Journal: Curr Opin Chem Biol

The concept of molecular diversity has been integrated in drug discovery efforts for many years. Applications of molecular diversity have been used to identify compounds for screening and to select compounds to augment proprietary collections. These early efforts were crude and suffered from a number of faults, but their evolution has, over the years, led to an improvement in the computational procedures used to identify new commercial compounds for acquisition. Although not much has recently been written about modern methods for augmenting compound collections, this activity is still a very relevant and important task to those involved with the development of compound collections. This review focuses on the process and software used to identify compounds deemed worthy of acquisition.

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The impact of natural products upon modern drug discovery.

Publication Date: 2008 Apr 16 PMID: 18423384
Authors: Ganesan, A.
Journal: Curr Opin Chem Biol

In the period 1970-2006, a total of 24 unique natural products were discovered that led to an approved drug. We analyze these successful leads in terms of drug-like properties, and show that they can be divided into two equal subsets. The first falls in the 'Lipinski universe' and complies with the Rule of Five. The second is a 'parallel universe' that violates the rules. Nevertheless, the latter compounds remain largely compliant in terms of logP and H-bond donors, highlighting the importance of these two metrics in predicting bioavailability. Natural products are often cited as an exception to Lipinski's rules, and we believe this is because nature has learned to maintain low hydrophobicity and intermolecular H-bond donating potential when it needs to make biologically active compounds with high molecular weight and large numbers of rotatable bonds. In addition, natural products are more probable than pure synthetic compounds to resemble biosynthetic intermediates or endogenous metabolites, and hence take advantage of active transport mechanisms. Interestingly, the natural product leads in the Lipinski and parallel universe had an identical success rate (50%) in delivering an oral drug.

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