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J Med Chem. 2012 Aug 23;55(16):7010-20. doi: 10.1021/jm3003069. Epub 2012 Aug 3.

Identifying novel adenosine receptor ligands by simultaneous proteochemometric modeling of rat and human bioactivity data.

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  • 1Division of Medicinal Chemistry, Leiden/Amsterdam Center for Drug Research, Einsteinweg 55, 2333 CC, Leiden, The Netherlands.


The four subtypes of adenosine receptors form relevant drug targets in the treatment of, e.g., diabetes and Parkinson's disease. In the present study, we aimed at finding novel small molecule ligands for these receptors using virtual screening approaches based on proteochemometric (PCM) modeling. We combined bioactivity data from all human and rat receptors in order to widen available chemical space. After training and validating a proteochemometric model on this combined data set (Q(2) of 0.73, RMSE of 0.61), we virtually screened a vendor database of 100910 compounds. Of 54 compounds purchased, six novel high affinity adenosine receptor ligands were confirmed experimentally, one of which displayed an affinity of 7 nM on the human adenosine A(1) receptor. We conclude that the combination of rat and human data performs better than human data only. Furthermore, we conclude that proteochemometric modeling is an efficient method to quickly screen for novel bioactive compounds.

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