Cannabinoids and/or endocannabinoids belong to a very large class of chemical compounds with diverse activity within our body including appetite stimulation, motor control, anxiety and depression attenuation, and relief to an array of symptoms such as pain, nausea, and inflammation. The variance in their activity is suggested to stem from the fact that different compounds from this class promote distinct conformations of canabinoid receptors, which may result in different signaling pathways (also called biased signaling). As such, these compounds have great potential therapeutic benefits. However, the molecular mechanisms underlying this differential signaling and its regulation by different ligands are not fully understood.
Our goal is to study the binding modes and affinity of different cannabinoids and/or endocannabinoids to cannabinoid receptors and further our understanding of the relation between the binding and the resulting activity. Our recent study for example, focused on two enantiomers, HU-308 and HU-433, that selectively bind type 2 cannabinoid receptor (CB2) and serve as anti-osteoporotic and anti-inflammatory. We tried to explain the puzzling fact that the binding affinity of HU-433 to CB2 is lower than that of HU-308, yet, it induces higher activity. Our studies identified two different binding poses within the receptor; one which seems to induce activity (Fig. B) and one with higher affinity, which may not induce any activity (Fig. A). A different question we were studying recently relates to identification of the binding mode of a ligand that binds allosterically outside the orthosteric receptor binding pocket. We believe that such studies may lead to utilization of pathway-biased ligands which has great potential for the development of selective therapeutic agents. Due to the special character of our research tools, we are not limited to any particular system and are therefore open to collaborations.
- Hebrew University of Jerusalem, Jerusalem, Israel
- Tel Aviv University, Tel Aviv, Israel
- Institute of Pharmaceutical Education and Research, Hajipur, India