Library lead-like

Horio, K., Muta, H., Goto, J. and Noriaki, H. (2007) A simple method to improve the odds in finding Lead-Like compounds from chemical libraries. Chemical e[ Pharmaceutical Bulletin, 55, 980-984. 

Stocks, M. J., Wilden, G. R. H, Pairaudeau, G., Perry, M. W. D, Steele, J., Stone-hous, J. P. (2009) A practical method for targeted library design balancing lead-like properties with diversity. ChemMedChem 4, 800-808. 

What kind of chemistry and reagents will then be capable of delivering arrays of compounds suitable for the identification of high-quality leads as outlined above As discussed in the introduction, for the preparation of highly diverse, lead-like libraries the incorporation of pharmacophore-rich reagents into the final products is required. The majority of important... 

Cheminformatics methods are required to design screening libraries, enrich existing libraries, select diverse or focused subsets, and pre- or post-filter undesired or reactive compounds. At present more than 10 million unique compounds are commercially available for screening (http //www.emolecules.com/, http //www.chemnavigator.com) and the theoretical number of synthetically tractable compounds even with lead-like properties is enormous (Bleicher et al., 2003 Fink, Bruggesser, and Reymond, 2005). 

In practice, an HTS collection of microclusters around diverse scaffolds provides a certain redundancy in noisy primary HTS data and facilitates the data analysis methods described above to identify active series. Recent library design efforts have shifted away from the optimal diversity approach and focus more on scaffold representation, high quality lead-like (Hann and Oprea, 2004) compounds, synthetic feasibility, and smart focused libraries to provide the best starting points for medicinal chemistry (Davies, Glick, and Jenkins 2006 Schnur, 2008). 

The selection and quality of a screening library with drug-like and lead-like structures is a critical endeavour. The features of drug-like and lead-like structures continue to be better defined, at the same time as the diversity of drug-like and lead-like molecular space continues to be explored and categorised. Other areas of development focus on the discovery of small molecules suitable for modulating protein-protein interactions, with a greater focus on natural product-like compounds. 

In parallel, hits are nominated from the group of actives, and chemical optimization is begun, to generate optimized leads. Ideally, the biased library consists of lead-like compounds and allows an efficient, short optimization program. We can anticipate that this parallel approach in chemical biology will lead to time reduction by 3.5 years as compared to the classical linear approach. 

The key properties of our ion channel library, namely molecular weight, polar surface area, clogP, and number of hydrogen bond acceptors and donors, are within the lead-like range of compounds (Figure 8.14) [59]. A purity analysis of a small... 

Hard filters are the most stringent in-silico filters and are used to shape the property profile of screening or combinatorial libraries and to prune hit lists from primary screening. They are derived from ID and 2D molecular properties (molecular weight, number of H-bond donors/acceptors, number of rotatable bonds, and so forth) and, as is described below, they are commonly used to reduce the number of false positive hits and to favor lead-like or drug-like chemotypes. 

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