LiPE
LiPE [1] is the abbreviation of Lipophilic Efficiency (sometimes refered to as LLE or ligand-lipophilicity efficiency[2]) and is a parameter used in drug design and drug discovery to evaluate the quality of research compounds, linking potency and lipophilicity in an attempt to estimate druglikeness. For a given compound LiPE is defined as the pIC50 (or pEC50) of interest minus the cLogP of the compound.
- <math>\ LiPE = pIC50 - cLogP </math>
LiPE is used to compare compounds of different potencies (pIC50s) and lipophilicities (cLogP). High potency (high value of pIC50) is a desirable attribute in drug candidates, as it reduces the risk of non-specific, off-target pharmacology at a given concentration. When associated with low clearance, high potency also allows for low total dose which lowers the risk of idiosyncratic drug reaction[3][4].
On the other hand, cLogP is a estimate of a compound's overall lipophilicity, a value that influence its behavior in a range of biological processes relevant to a drug discovery, such as solubility, permeability through biological membranes, hepatic clearance, lack of selectivity and non-specific toxicity[5]. For oral drugs, a cLogP value comprised between 2 and 3 is often considered optimal to achieve a compromise between permeability and first-pass clearance.
LiPE allows to capture both values in a single parameter, and empirical evidence suggest that quality drug candidates have a high LiPE (>6); this value corresponds to a a compound with a pIC50 of 8 and a cLogP of 2. Plotting cLogP against pIC50 for a range of compounds allows to rank series and individual compounds.
References
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- ↑ Ryckmans, T.; et al. (2009). "Rapid assessment of a novel series of selective CB2 agonists using parallel
synthesis protocols: A Lipophilic Efficiency (LipE) analysis". Bioorg. Med. Chem. Lett. 19: 4406–4409. doi:10.1016/j.bmcl.2009.05.062. line feed character in
|title=at position 76 (help) - ↑ Leeson, P. D.; et al. (2007). "The influence of drug-like concepts on
decision-making in medicinal chemistry". Nat. Rev. Drug Disc. 7: 881–890. doi:10.1038/nrd2445. line feed character in
|title=at position 39 (help) - ↑ Uetrecht, J. (2001). "Prediction of a new drug's potential to cause idiosyncratic reactions". Curr. Opin. Drug Disc. Devel. 4: 55–59.
- ↑ Uetrecht, J. (2008). "Idiosyncratic Drug Reactions: Past, Present, and Future". Chem. Res. Toxicol. 21: 84–92.
- ↑ Hughes, J. D.; et al. (2008). "Physiochemical drug properties associated with in vivo toxicological outcomes". Bioorg. Med. Chem. Lett. 8: 4872–5. doi:10.1016/j.bmcl.2008.07.071.
