Drug-like libraries

Combinatorial chemistry is applying a multitude of approaches such as diversity libraries, drug-like libraries and combinatorial subset selection. ... 

The challenge in the synthesis of chemical libraries is the vast number of different, potentially drug-like small molecules which is estimated to be as high as 1060. As all of these molecules can never be synthesized and tested, it is essential to define criteria for the composition of libraries spanning the biologically relevant areas of the chemical space most efficiently. An important criterion of a compound library is its chemical diversity, a term describing the similarity or dissimilarity of all library components. Thus, chemical diversity expresses how well a library represents all theoretical possibilities within the chemical property space. A library with low... 

Computational approaches towards the rational design of drug-like compound libraries. Comb. Chem. High-Throughput Screen. 2001, 4, 453 75. 

Mitchell, T., Showell, G. A. Design strategies for building drug-like chemical libraries. Curr. Opin. Drug Discov. Dev. 2001, 4, 314-318. 

Matter, H., Baringhaus, K. H., Naumann, T., Kiabunde, T., Pirard, B., Computational approaches towards the rational design of drug-like compound libraries, Comb. Chem. High Throughput Screen. 2001, 4, 453-475. 

The genesis of in silico oral bioavailability predictions can be traced back to Lip-inski s Rule of Five and others qualitative attempts to describe drug-like molecules [13-15]. These processes are useful primarily as a qualitative tool in the early stage library design and in the candidate selection. Despite its large number of falsepositive results, Lipinski s Rule of Five has come into wide use as a qualitative tool to help the chemist design bioavailable compounds. It was concluded that compounds are most likely to have poor absorption when the molecular weight is >500, the calculated octan-l-ol/water partition coefficient (c log P) is >5, the number of H-bond donors is >5, and the number of H-bond acceptors is >10. Computation of these properties is now available as an ADME (absorption, distribution, metabolism, excretion) screen in commercial software such as Tsar (from Accelrys). The rule-of-5 should be seen as a qualitative, rather than quantitative, predictor of absorption and permeability [16, 17]. 

Fig. 18.2 Elaboration-based strategies. Left In SHAPES screening [3], simple drug-like scaffolds are screened using ligand-detected experiments. In the follow-up step, information about binding scaffolds is used to design a follow-up library comprised of analogous compounds. Successive rounds of screening lead to increasingly complex...

Fig. 18.3 Variation-based strategies. Left The SHAPES Linking Library [11] consists of drug-like scaffolds connected by linkers that are amenable to combinatorial chemistry (dashed line). Hits are followed up by synthesizing a combinatorial library in which the scaffolds are systematically varied. Center Directed Combinatorial Librari es [12] are comprised of scaffolds containing multiple sites for substituents. Hits are followed up by...

The SHAPES Linking Library was designed to facilitate the use of combinatorial chemistry to follow up screening hits [11]. This library consists primarily of commercially available compounds containing two drug-like scaffolds connected by a linkage that is synthetically accessible. To construct this library, a database of commercially available compounds was filtered to select for drug-likeness and the presence of the desired molecular... 

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