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About the Authors:
Silvia Paoletta
Affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
Dilip K. Tosh
Affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
Daniela Salvemini
Affiliation: Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, Saint Louis, Missouri, United States of America
Kenneth A. Jacobson
* E-mail: [email protected]
Affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
Introduction
The potential liabilities and advantages of off-target effects of known drugs have been a growing concern in drug development [1]. Often it is difficult to gauge the combined effects of more than one drug action in complex in vivo systems, and off-target activities are more commonly viewed as detrimental in the drug discovery process. Therefore, there is interest in understanding the factors affecting drug promiscuity in order to avoid those liabilities early in the drug discovery process. Peters et al. have recently analyzed large datasets of drug-like compounds to identify molecular properties and structural motifs characterizing promiscuous compounds [2]. Keiser et al. have found by in vitro screening and prediction new molecular targets of >3600 approved and investigational drugs based on chemical similarity [3]. In some cases, a given off-target activity could be beneficial if it contributes to the net biological effect of the agent in a positive manner [4]. Moreover, off-target effects can also serve as leads for repurposing of known biologically active scaffolds at new molecular targets. This approach was carried out in the past empirically (for example, using privileged scaffolds such as 1,4-dihydropyridines [5]) and can now be performed in a more systematic way with detailed knowledge of the 3D structures of many drug targets including G protein-coupled receptors (GPCRs) [6].
In the course of developing the structure-activity relationship (SAR) of adenosine and adenine derivatives as ligands of nanomolar affinity at the adenosine receptors (ARs) [7], possible off-target binding activities at other GPCRs became evident at higher concentrations than their Ki values...