Computer-aided design of liposomal drugs: In silico prediction and experimental validation of drug candidates for liposomal remote loading

JOURNAL OF CONTROLLED RELEASE

卷:173

Article

Cern, Ahuva^1,2  Barenholz, Yechezkel¹  Tropsha, Alexander³  Goldblum, Amiram² 

[1] Hebrew Univ Jerusalem, Hadassah Med Sch, Dept Biochem, Lab Membrane & Liposome Res,IMRIC, IL-91010 Jerusalem, Israel

[2] Hebrew Univ Jerusalem, Inst Drug Res, Mol Modeling & Drug Design Lab, Jerusalem, Israel

[3] Univ N Carolina, UNC Eshelman Sch Pharm, Lab Mol Modeling, Chapel Hill, NC USA

关键词: Liposomes;    Remote loading;    QSPR;    Virtual screening;    Iterative Stochastic Elimination;    k-Nearest Neighbors;   

DOI  :  10.1016/j.jconrel.2013.10.029

来源: Elsevier

【 摘 要 】

Previously we have developed and statistically validated Quantitative Structure Property Relationship (QSPR) models that correlate drugs' structural, physical and chemical properties as well as experimental conditions with the relative efficiency of remote loading of drugs into liposomes (Cern et al., J. Control. Release 160 (2012) 147-157). Herein, these models have been used to virtually screen a large drug database to identify novel candidate molecules for liposomal drug delivery. Computational hits were considered for experimental validation based on their predicted remote loading efficiency as well as additional considerations such as availability, recommended dose and relevance to the disease. Three compounds were selected for experimental testing which were confirmed to be correctly classified by our previously reported QSPR models developed with Iterative Stochastic Elimination (ISE) and k-Nearest Neighbors (kNN) approaches. In addition, 10 new molecules with known liposome remote loading efficiency that were not used by us in QSPR model development were identified in the published literature and employed as an additional model validation set. The external accuracy of the models was found to be as high as 82% or 92%, depending on the model. This study presents the first successful application of QSPR models for the computer-model-driven design of liposomal drugs. (C) 2013 Elsevier B.V. All rights reserved.

【 授权许可】

Free