Chemistry:Lipophilic efficiency
Lipophilic efficiency[1] (LiPE), sometimes referred to as ligand-lipophilicity efficiency (LLE) 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.[2][3] For a given compound LiPE is defined as the pIC50 (or pEC50) of interest minus the LogP of the compound.
- [math]\displaystyle{ \ce{LiPE} = \ce{pIC50} - \log P }[/math]
In practice, calculated values such as cLogP or calculated LogD are often used instead of the measured LogP or LogD. LiPE is used to compare compounds of different potencies (pIC50s) and lipophilicities (LogP). 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.[4][5]
On the other hand, LogP is an 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.[6] For oral drugs, a LogP value comprised between 2 and 3 is often considered optimal to achieve a compromise between permeability and first-pass clearance.
LiPE allows capturing both values in a single parameter, and empirical evidence suggest that quality drug candidates have a high LiPE (>6); this value corresponds to a compound with a pIC50 of 8 and a LogP of 2. Plotting LogP against pIC50 for a range of compounds allows ranking series and individual compounds.
An alternative equation uses the logarithm of the ratio of potency (measured as binding energy) and the partition coefficient to compute a lipophilic ligand efficiency index (LE) with a different scale.[7]
- [math]\displaystyle{ \ce{LElipo} = \log\left(\frac{-\Delta G}{P}\right) }[/math]
The following review discusses LipE in the context of other compound efficiency metrics.[8]
References
- ↑ "Rapid assessment of a novel series of selective CB(2) agonists using parallel synthesis protocols: A Lipophilic Efficiency (LipE) analysis". Bioorganic & Medicinal Chemistry Letters 19 (15): 4406–9. August 2009. doi:10.1016/j.bmcl.2009.05.062. PMID 19500981.
- ↑ Edwards MP, Price DA (2010). "Role of Physicochemical Properties and Ligand Lipophilicity Efficiency in Addressing Drug Safety Risks". Annual Reports in Medicinal Chemistry 45: 381–391. doi:10.1016/S0065-7743(10)45023-X. ISBN 9780123809025.
- ↑ "The influence of drug-like concepts on decision-making in medicinal chemistry". Nature Reviews. Drug Discovery 6 (11): 881–90. November 2007. doi:10.1038/nrd2445. PMID 17971784.
- ↑ "Prediction of a new drug's potential to cause idiosyncratic reactions". Current Opinion in Drug Discovery & Development 4 (1): 55–9. January 2001. PMID 11727323.
- ↑ "Idiosyncratic drug reactions: past, present, and future". Chemical Research in Toxicology 21 (1): 84–92. January 2008. doi:10.1021/tx700186p. PMID 18052104.
- ↑ "Physiochemical drug properties associated with in vivo toxicological outcomes". Bioorganic & Medicinal Chemistry Letters 18 (17): 4872–5. September 2008. doi:10.1016/j.bmcl.2008.07.071. PMID 18691886.
- ↑ "Drug efficiency indices for improvement of molecular docking scoring functions". Journal of Computational Chemistry 31 (1): 174–84. January 2010. doi:10.1002/jcc.21306. PMID 19422000.
- ↑ "Setting expectations in molecular optimizations: Strengths and limitations of commonly used composite parameters". Bioorganic & Medicinal Chemistry Letters 23 (21): 5980–91. November 2013. doi:10.1016/j.bmcl.2013.08.029. PMID 24018190.
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