Computational investigation on the binding modes of Rimonabant analogs with CB1 and CB2

Abstract

The human cannabinoid G-protein-coupled receptor 1 (CB1) is highly expressed in central nervous system. CB1-selective antagonists show therapeutic promise in a wide range of disorders, such as obesity-related metabolic disorders, dyslipidemia, drug abuse, and type 2 diabetes. Rimonabant (SR141716A), MJ08, and MJ15 are selective CB1 antagonists with selectivity >1,000-folds over CB2 despite 42% sequence identity between CB1 and CB2. The integration of homology modeling, automated molecular docking, and molecular dynamics simulation were used to investigate the binding modes of these selective inverse agonists/antagonists with CB1 and CB2 and their selectivity. Our analyses showed that the hydrophobic interactions between ligands and hydrophobic pockets of CB1 account for the main binding affinity. In addition, instead of interacting with ligands directly as previously reported, the Lys192 in CB1 was engaged in indirect interactions with ligands to keep inactive-state CB1 stable by forming the salt bridge with Asp176 . Lastly, our analyses indicated that the selectivity of these antagonists came from the difference in geometry shapes of binding pockets of CB1 and CB2. The present study could guide future experimental works on these receptors and has the guiding significance for the design of functionally selective drugs targeting CB1 or CB2 receptors.

“Photo-Rimonabant”: Synthesis and Biological Evaluation of Novel Photoswitchable Molecules Derived from Rimonabant Lead to a Highly Selective and Nanomolar “Cis-On” CB1R Antagonist

“…Additionally, S123 (which is predicted to form hydrogen bonds with 16a in CB 1 ) is replaced by C40 at the equivalent position in CB 2 , which may affect hydrogen bond formation and promote CB 1 selectivity. These observations are congruent with the incompatibility of the CB 2 binding pocket geometry with the extended conformation of rimonabant, as it has been suggested in the literature …”

“…These observations are congruent with the incompatibility of the CB 2 binding pocket geometry with the extended conformation of rimonabant, as it has been suggested in the literature. 56…”

Prediction of the Binding Affinities and Selectivity for CB1 and CB2 Ligands Using Homology Modeling, Molecular Docking, Molecular Dynamics Simulations, and MM-PBSA Binding Free Energy Calculations

“…23 The investigation and determination of GPCR structures are hindered due to the nature of membrane proteins and the transient and dynamic interactions between GPCRs and their ligands, which are difficult to capture, and post-technical challenges. 24 Regarding CBs, currently there are only four resolved CB1 crystal structures and one resolved CB2 crystal structure in the Protein Data Bank. The lack of crystal structures, especially for CB2, is an obstacle that researchers have to overcome to explore their conformational change and downstream signaling when they are bound with agonists, antagonists, or even allosteric modulators at a topographically distinct binding site.…”

“…By applying molecular modeling simulations, a previous study reported for the first time the binding modes of rimonabant analogues with CB1 and CB2. 24 However, both reported structures of CB1 and CB2 in their inactive conformations were constructed from the crystal structure of the sphingosine-1-phosphate receptor 1 using homology modeling, and only four ligands with selectivity to CB1 or CB2 were involved. In this study, we investigated CB1 and CB2 in both the inactive and active conformations via molecular dynamics (MD) simulations and conducted free energy analysis with an aim to systematically compare the binding features, conformations, potency, and selectivity of the two cannabinoid receptors.…”

Cannabinoids and Cannabinoid Receptors: The Story so Far

“…Although the 2016 release of the first CB 1 crystal structure increased the scope of modeling opportunities, homology modeling has continued to be an important approach to obtain accurate 3D structures in the absence of experimental structures, especially for the phytocannabinoids. In 2018, Liu and coworkers used a combination of sequence alignment and homology modeling of the S1P1 crystal structure (PDB: 3V2W ) ( Hanson et al., 2012 ) to investigate the binding modes of rimonabant analogs as selective inverse agonists/antagonists for CB 1 ( Liu et al., 2018 ). Their CB 1 model was validated by superimposing the model and the crystal structure ( PDB : 5TGZ ).…”