亲脂效率 - 维基百科，自由的百科全书

亲脂效率^[1]（英文：Lipophilic efficiency，LiP），也称为配体亲脂效率（英文：Ligand-lipophilicity efficicency，LLE），是药物设计和药物发现中用于评估研究化合物质量的参数，将效价和亲脂性联系起来以评估药物相似性。^[2]^[3]对于给定的化合物，LiPE定义为关注的pIC₅₀（或pEC₅₀）与化合物LogP的差值。

{\ce {LiPE}}={\ce {pIC50}}-\log P

在研发实践中，通常使用计算值（例如cLogP或计算出的 cLogD）来代替测量的LogP或LogD。LiPE用于比较不同效价（pIC₅₀s）和亲脂性（LogP）的化合物。高效价，即pIC₅₀值高是候选药物的理想属性，因为在给定的药物浓度下，高效价意味着降低了非特异性和脱靶的药理学风险。当药物与低清除率相关时，高效价也允许更低的用药剂量，从而降低特异质药物反应的风险。^[4]^[5]

另一方面，LogP代表了化合物总体亲脂性的估算，该值会影响药物发现中一系列生物过程中的行为，例如溶解度、生物膜渗透性、肝清除率、缺乏选择性和非-特异性毒性。^[6]对于口服药物，LogP值介于2和3之间通常被认为是实现渗透性和首过清除率之间折衷的最佳选择。

经验证据表明优质候选药物具有高LiPE(>6)；该值对应于 pIC₅₀ = 8且LogP = 2的化合物。绘制一系列化合物的 LogP对pIC₅₀的关系图可以对一个系列和单个化合物进行优先等级排序。

另一个方程使用效能比（以结合能测量）和分配系数的对数来计算具有不同比例的亲脂性配体效率指数（LE）。 ^[7]

{\ce {LElipo}}=\log \left({\frac {-\Delta G}{P}}\right)

其他复合效率指标的背景下的LipE。^[8]

参考文献

^ Ryckmans T, Edwards MP, Horne VA, Correia AM, Owen DR, Thompson LR, Tran I, Tutt MF, Young T. Rapid assessment of a novel series of selective CB(2) agonists using parallel synthesis protocols: A Lipophilic Efficiency (LipE) analysis. Bioorganic & Medicinal Chemistry Letters. August 2009, 19 (15): 4406–9. PMID 19500981. doi:10.1016/j.bmcl.2009.05.062.
^ Edwards MP, Price DA. Role of Physicochemical Properties and Ligand Lipophilicity Efficiency in Addressing Drug Safety Risks. Annual Reports in Medicinal Chemistry. 2010, 45: 381–391. ISBN 9780123809025. doi:10.1016/S0065-7743(10)45023-X.
^ Leeson PD, Springthorpe B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nature Reviews. Drug Discovery. November 2007, 6 (11): 881–90. PMID 17971784. S2CID 205476574. doi:10.1038/nrd2445.
^ Uetrecht J. Prediction of a new drug's potential to cause idiosyncratic reactions. Current Opinion in Drug Discovery & Development. January 2001, 4 (1): 55–9. PMID 11727323.
^ Uetrecht J. Idiosyncratic drug reactions: past, present, and future. Chemical Research in Toxicology. January 2008, 21 (1): 84–92. PMID 18052104. doi:10.1021/tx700186p.
^ Hughes JD, Blagg J, Price DA, Bailey S, Decrescenzo GA, Devraj RV, Ellsworth E, Fobian YM, Gibbs ME, Gilles RW, Greene N, Huang E, Krieger-Burke T, Loesel J, Wager T, Whiteley L, Zhang Y. Physiochemical drug properties associated with in vivo toxicological outcomes. Bioorganic & Medicinal Chemistry Letters. September 2008, 18 (17): 4872–5. PMID 18691886. doi:10.1016/j.bmcl.2008.07.071.
^ García-Sosa AT, Hetényi C, Maran U. Drug efficiency indices for improvement of molecular docking scoring functions. Journal of Computational Chemistry. January 2010, 31 (1): 174–84. PMID 19422000. S2CID 19092197. doi:10.1002/jcc.21306.
^ Shultz MD. Setting expectations in molecular optimizations: Strengths and limitations of commonly used composite parameters. Bioorganic & Medicinal Chemistry Letters. November 2013, 23 (21): 5980–91. PMID 24018190. doi:10.1016/j.bmcl.2013.08.029.

[pmid19500981-1] Ryckmans T, Edwards MP, Horne VA, Correia AM, Owen DR, Thompson LR, Tran I, Tutt MF, Young T. Rapid assessment of a novel series of selective CB(2) agonists using parallel synthesis protocols: A Lipophilic Efficiency (LipE) analysis. Bioorganic & Medicinal Chemistry Letters. August 2009, 19 (15): 4406–9. PMID 19500981. doi:10.1016/j.bmcl.2009.05.062.

[2] Edwards MP, Price DA. Role of Physicochemical Properties and Ligand Lipophilicity Efficiency in Addressing Drug Safety Risks. Annual Reports in Medicinal Chemistry. 2010, 45: 381–391. ISBN 9780123809025. doi:10.1016/S0065-7743(10)45023-X.

[pmid17971784-3] Leeson PD, Springthorpe B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nature Reviews. Drug Discovery. November 2007, 6 (11): 881–90. PMID 17971784. S2CID 205476574. doi:10.1038/nrd2445.

[pmid11727323-4] Uetrecht J. Prediction of a new drug's potential to cause idiosyncratic reactions. Current Opinion in Drug Discovery & Development. January 2001, 4 (1): 55–9. PMID 11727323.

[pmid18052104-5] Uetrecht J. Idiosyncratic drug reactions: past, present, and future. Chemical Research in Toxicology. January 2008, 21 (1): 84–92. PMID 18052104. doi:10.1021/tx700186p.

[pmid18691886-6] Hughes JD, Blagg J, Price DA, Bailey S, Decrescenzo GA, Devraj RV, Ellsworth E, Fobian YM, Gibbs ME, Gilles RW, Greene N, Huang E, Krieger-Burke T, Loesel J, Wager T, Whiteley L, Zhang Y. Physiochemical drug properties associated with in vivo toxicological outcomes. Bioorganic & Medicinal Chemistry Letters. September 2008, 18 (17): 4872–5. PMID 18691886. doi:10.1016/j.bmcl.2008.07.071.

[pmid19422000-7] García-Sosa AT, Hetényi C, Maran U. Drug efficiency indices for improvement of molecular docking scoring functions. Journal of Computational Chemistry. January 2010, 31 (1): 174–84. PMID 19422000. S2CID 19092197. doi:10.1002/jcc.21306.

[pmid24018190-8] Shultz MD. Setting expectations in molecular optimizations: Strengths and limitations of commonly used composite parameters. Bioorganic & Medicinal Chemistry Letters. November 2013, 23 (21): 5980–91. PMID 24018190. doi:10.1016/j.bmcl.2013.08.029.

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