Drugs as fragments

Siegel, M. G., and Vieth, M. (2007). Drugs in other drugs a new look at drugs as fragments. Drug Discovery Today 12, 71-79. 

The editors have chosen topics from both important therapeutic areas and from work that advances the discipline of medicinal chemistry. For example, cancer, metabolic syndrome and Alzheimer s disease are fields in which academia and industry are heavily invested to discover new drugs because of their considerable unmet medical need. The editors have therefore prioritized covering new developments in medicinal chemistry in these fields. In addition, important advances in the discipline, such as fragment-based drug design and other aspects of new lead-seeking approaches, are also planned for early volumes in this series. Each volume thus offers a unique opportunity to capture the most up-to-date perspective in an area of medicinal chemistry. 

Fragments should be composed of drug-like chemical matter because substantial parts of a fragment hit will end up in the final lead candidate for in vivo assays. Therefore, we selected our NMR screening library from commercially available compound repositories that have a proven track record in lead discovery (e.g. by many years of use in HTS) and also as they include structures and substructures that occur in known marketed drugs, as well as in clinical and preclinical candidates. This ensures that the fragment library is built on several decades of experience in drug discovery. 

An initial strategy to optimize the drugabil-ity of (2) focused on two fragments with potential liabilities. The 4-hydroxy phenyl piperidine is also present in haloperidol and implicated with neurotoxicity, and the tricyclic dibenzothiepine is a common feature of CNS-active drugs. As indicated in Table 4.2, removal of the 4 -hydroxy led to a complete loss of potency against CCRl. 

However, before proceeding further, it is useful to ask exactly how to define FBDD. The challenge lies in the fact that more than 400 approved drugs could be defined as fragments using the Rule of 3 described above, yet few if any were discovered using fragment-based approaches. 

That said, X-ray crystallography provides the most detailed information about protein-ligand interactions and has established itself as an essential tool for FBDD. In the next few years, many more of the drugs that enter the clinic will have started as fragments and advanced with the aid of crystallography. Hopefully, some of these will soon be approved and begin making a serious difference to human health. 

Up until this point we have described how molecules may be selected to be similar or diverse and how they may be filtered and scored as to how like categories of molecule (drug, lead, fragment, natural product) they are. The following sections will describe how these methods are applied to the design of individual arrays and entire screening collections. 

It has already been discussed under section 2.1. (a) that construction reactions essentially establish carbon-carbon skeletons (bonds) in a tai et-drug-molecules those reactions that specifically cleave carbon-carbon skeletons (bonds) are usually termed as fragmentation reactions . In other words, the former enjoys its existence and importance to build up desired C—C skeletons and, therefore, are absolutely necessary in a synthesis however, the latter causes degradation or split-up of C—C skeletons and they also possess certain vital synthetic utility. There are, in fact, two important reactions that are particularly useful in affording the fragmentation reactions, such as ... 

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