The application of a 3D-QSAR (autoMEP/PLS) approach as an efficient pharmacodynamic-driven filtering method for small-sized virtual library: Application to a lead optimization of a human A₃ adenosine receptor antagonist

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• 作者：Stefano Moro ; Magdalena Bacilieri ; Barbara Cacciari ; Chiara Bolcato ; Claudia Cusan ; Giorgia Pastorin ; Karl-Norbert Klotz and Giampiero Spalluto
• 关键词：GPCR ; A₃ adenosine receptor antagonist ; 3D-QSAR ; Molecular modeling
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2006
• 出版时间：15 July 2006
• 年：2006
• 卷：14
• 期：14
• 页码：4923-4932
• 全文大小：300 K

文摘

We have recently reported that the combination of molecular electrostatic potential (MEP) surface properties (autocorrelation vectors) with the conventional partial least squares (PLS) analysis can be used to produce a robust ligand-based 3D structure–activity relationship (autoMEP/PLS) for the prediction of the human A₃ receptor antagonist activities. Here, we present the application of the 3D-QSAR (autoMEP/PLS) approach as an efficient and alternative pharmacodynamic filtering method for small-sized virtual library. For this purpose, a small-sized combinatorial library (841 compounds) was derived from the scaffold of the known human A₃ antagonist pyrazolo-triazolo-pyrimidines. The most interesting analogues were further prioritized for synthesis and pharmacological characterization. Remarkably, we have found that all the newly synthetized compounds are correctly predicted as potent human A₃ antagonists. In particular, two of them are correctly predicted as sub-nanomolar inhibitors of the human A₃ receptor.