4.7 Article

Negative allosteric modulators of cannabinoid receptor 2: protein modeling, binding site identification and molecular dynamics simulations in the presence of an orthosteric agonist

Journal

JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS
Volume 38, Issue 1, Pages 32-47

Publisher

TAYLOR & FRANCIS INC
DOI: 10.1080/07391102.2019.1567384

Keywords

CB2 receptor; CB2 allosteric modulator; docking; G-protein-coupled receptor; molecular dynamics

Funding

  1. Institutional Development Award (IDeA) [P20GM104932]
  2. National Institute of General Medical Sciences (NIGMS), a component of the National Institutes of Health (NIH) [R15GM119061]
  3. National Science Foundation (NSF) Major Research Infrastructure Grant [CHE-1338056]
  4. Extreme Science and Engineering Discovery Environment (XSEDE) [MCB140248]
  5. Research Facilities Improvements Program from NIH National Center for Research Resources [C06 RR-14503]

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Selective activation of the cannabinoid receptor subtype 2 (CB2) shows promise for treating pain, inflammation, multiple sclerosis, cancer, ischemic/reperfusion injury and osteoporosis. Target selectivity and off-target side effects are two major limiting factors for orthosteric ligands, and therefore, the search for allosteric modulators (AMs) is a widely used drug discovery approach. To date, only a limited number of negative CB2 AMs have been identified, possessing only micromolar activity at best, and the CB2 receptor's allosteric site(s) are not well characterized. Herein, we used computational approaches including receptor modeling, site mapping, docking, molecular dynamics (MD) simulations and binding free energy calculations to predict, characterize and validate allosteric sites within the complex of the CB2 receptor with bound orthosteric agonist CP55,940. After docking of known negative CB2 allosteric modulators (NAMs), dihydro-gambogic acid (DHGA) and trans-beta-caryophyllene (TBC) (note that TBC also shows agonist activity), at the predicted allosteric sites, the best total complex with CB2, CP55,940 and NAM was embedded into a hydrated lipid bilayer and subjected to a 200 ns MD simulation. The presence of an AM affected the CB2-CP55,940 complex, altering the relative positioning of the toggle switch residues and promoting a strong pi-pi interaction between Phe117(3.36) and Trp258(6.48). Binding of either TBC or DHGA to a putative allosteric pocket directly adjacent to the orthosteric ligand reduced the binding free energy of CP55,940, which is consistent with the expected effect of a negative AM. The identified allosteric sites present immense scope for the discovery of novel classes of CB2 AMs.

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