ADME absorption, distribution library design

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]. 

Effectiveness of ADME (absorption, distribution, metabolism, excretion) design implementation depends on whether chemistry protocol development or chemistry production is rate determining. If chemistry production is rate determining there will be excess validated protocols relative to library production. This means that protocols can be prioritized as to their ADME attractiveness and the least attractive protocols from an ADME perspective may never be translated into actual library production. However, protocol development and not library production is often the rate-determining step. This eventuality is unfortunate because there is an understandable reluctance to discontinue chemistry synthetic efforts because of a poor ADME experimental profile if considerable chemistry... 

With increasing importance being attached to the early detection of compounds likely to be problematic from an absorption, distribution, metabolism, and excretion (ADME) viewpoint, " at RPR we sought to apply computational measures for the prediction of intestinal absorption—a key requirement for an orally bioavailable compound—during the design of lead optimization libraries. To this end, we implemented the popular rule-of-5 criteria described by Lipinski et al. compound is deemed to fail the rule-of-5 check (and thereby to be possibly deficient from an oral absorption/permeability aspect) if it possesses two or more of the following features ... 

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