ADMET properties plasma protein binding

Hansch and Leo [13] described the impact of Hpophihdty on pharmacodynamic events in detailed chapters on QSAR studies of proteins and enzymes, of antitumor drugs, of central nervous system agents as well as microbial and pesticide QSAR studies. Furthermore, many reviews document the prime importance of log P as descriptors of absorption, distribution, metabolism, excretion and toxicity (ADMET) properties [5-18]. Increased lipophilicity was shown to correlate with poorer aqueous solubility, increased plasma protein binding, increased storage in tissues, and more rapid metabolism and elimination. Lipophilicity is also a highly important descriptor of blood-brain barrier (BBB) permeability [19, 20]. Last, but not least, lipophilicity plays a dominant role in toxicity prediction [21]. 

In a similar effort, researchers from the same company used AstraZeneca data and ADMET properties, namely, solubility, plasma protein binding, and lipophilicity (log D) from a pool of 50000 molecules in total [16]. In particular, a set of approximately 9000 side chains was identified by applying the fragmentation rules proposed in Retrosynthetic Combinatorial Analysis Procedure (RECAP) [26]. The MMPs were then generated easily by identifying compounds that contain any of the aforementioned predetermined Ust of side chains. The authors reported the most frequent side chain replacements, as well as the replacements that lead to an increase of the average property value, although their statistics were based on relatively low numbers of observations for each replacement (11-77). 

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