Molecular Origin of Drug Selectivity in Human Cannabinoid Receptors

Diwakar Shukla, University of Illinois at Urbana-Champaign

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Diwakar Shukla, Balaji Selvam, Chuankai Zhao, Shriyaa Mittal, Jiangyan Feng, Jiming Chen, Matthew Chan, Pouyan Khakbaz, Soumajit Dutta, Austin Weigle, Prateek Bansal, Amisha Patel, Xuenan Mi, Zhengyuan Xue

Cannabinoid receptor 1 (CB1) is a therapeutically relevant drug target to control pain, obesity and other
central nervous system disorders. However, due to the harmful side effects of full agonists (molecules
that activate CB1) and antagonists (molecules that deactivate CB1), no clinical drug that targets CB1 is
currently available on the market. One of the reasons for this lack of a selective and potent drugs targeting
CB1 is limited by mechanistic understanding of drug selectivity and molecular origin of partial agonism.
Therefore, we aim (1) to understand the molecular mechanism of CB1 selectivity with respect to
homologous cannabinoid receptor 2 (CB2) and (2) functional mechanism by which partial agonists such
as Δ⁹-tetrahydrocannabinol (Δ⁹-THC) modulate Cannabinoid receptors. Our research plan includes testing
multiple mechanistic hypotheses for origin of both drug selectivity and partial agonism in CBs using
extensive molecular dynamics simulations. In particular, we plan to perform simulations of apo receptors
activation mechanism, antagonist and partial agonist binding to these receptors. Simulations studies of
apo CBs would reveal the difference between activation mechanism of CB1 and CB2. Antagonist binding
and post binding changes (Holo) would show the selectivity profiles of these receptors. Partial agonist
binding study of CB1 would provide details about the binding pathways and interactions that reduce the
activity with respect to the agonists.