Binding Modes and Selectivity of Cannabinoid 1 (CB1) and Cannabinoid 2 (CB2) Receptor Ligands

Abstract

The cannabinoid (CB) receptors (CB 1 R and CB 2 R) represent a promising therapeutic target for several indications such as nociception and obesity. The ligands with nonselectivity can be traced to the high similarity in the binding sites of both cannabinoid receptors. Therefore, the need for selectivity, potency, and G-protein coupling bias has further complicated the design of desired compounds. The bias of currently studied cannabinoid agonists is seldom investigated, and agonists that do exhibit bias are typically nonselective. However, certain long-chain endocannabinoids represent a class of selective and potent CB 1 R agonists. The binding mode for this class of compounds has remained elusive, limiting the implementation of its binding features to currently studied agonists. Hence, in the present study, the binding poses for these long-chain cannabinoids, along with other interesting ligands, with the receptors have been determined, by using a combination of molecular docking and molecular dynamics (MD) simulations along with molecular mechanics-Poisson−Boltzmann surface area (MM-PBSA) binding free energy calculations. The binding poses for the long-chain cannabinoids implicate that a site surrounded by the transmembrane (TM)2, TM7, and extracellular loop (ECL)2 is vital for providing the long-chain ligands with the selectivity for CB 1 R, especially I267 of CB 1 R (corresponding to L182 of CB 2 R). Based on the obtained binding modes, the calculated relative binding free energies and selectivity are all in good agreement with the corresponding experimental data, suggesting that the determined binding poses are reasonable. The computational strategy used in this study may also prove fruitful in applications with other GPCRs or membrane-bound proteins.

Fast Prediction of Binding Affinities of the SARS-CoV-2 Spike Protein Mutant N501Y (UK Variant) with ACE2 and Miniprotein Drug Candidates

“…45−47 Additionally, to estimate the change in binding free energy with the miniprotein inhibitors, the available crystal structures of miniproteins LCB1 (RCSB: 7JZU) 7 and LCB3 (RCSB: 7JZM) 7 were energy-minimized, and their binding free energies with both the wild-type spike protein and the N501Y variant were estimated using the same methodology. Further, as shown previously, 21,47 the MM-PBSA calculations overestimated the absolute binding free energies. Nevertheless, we have previously reported a methodology that utilizes known in vitro experimental data to correct these overestimations using a linear regression equation, allowing for both accurate and precise protein/ligand and protein/protein binding affinity predictions.…”

Prediction of essential binding domains for the endocannabinoid N-arachidonoylethanolamine (AEA) in the brain cannabinoid CB1 receptor

“…Overall, the binding pose 1_H2/H3_HC could be the best candidate for the bioactive conformation of AEA at the CB1 receptor. This conclusion agrees with a recent study of the binding mode predictions of various AEA-like endocannabinoids guided by molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) binding free energy calculations [46]. The AEA binding mode in this study is quite similar to our AEA binding pose 1_H2/ H3_HC.…”

Mechanistic Understanding from Molecular Dynamics in Pharmaceutical Research 2: Lipid Membrane in Drug Design

“…In contrast to multi-pass (integral) membrane proteins, where considerable work has been performed, in particular the GPCR class of membrane proteins e.g., [885][886][887][888][889][890][891][892][893][894][895][896][897][898][899] (for review see references: [31,[900][901][902][903]), that are a very hot topic, peripheral and bitopic (single pass) membrane proteins, which constitute 43-45% of transmembrane proteins [883], are underrepresented in MD simulation studies.…”