Cannabinoid Receptor Subtype 2 (CB2R) in a Multitarget Approach: Perspective of an Innovative Strategy in Cancer and Neurodegeneration

Abstract

The cannabinoid receptor subtype 2 (CB2R) represents an interesting and new therapeutic target for its involvement in the first steps of neurodegeneration as well as in cancer onset and progression. Several studies, focused on different types of tumors, report a promising anticancer activity induced by CB2R agonists due to their ability to reduce inflammation and cell proliferation. Moreover, in neuroinflammation, the stimulation of CB2R, overexpressed in microglial cells, exerts beneficial effects in neurodegenerative disorders. With the aim to overcome current treatment limitations, new drugs can be developed by specifically modulating, together with CB2R, other targets involved in such multifactorial disorders. Building on successful case studies of already developed multitarget strategies involving CB2R, in this Perspective we aim at prompting the scientific community to consider new promising target associations involving HDACs (histone deacetylases) and σ receptors by employing modern approaches based on molecular hybridization, computational polypharmacology, and machine learning algorithms.

DeLA-Drug: A Deep Learning Algorithm for Automated Design of Druglike Analogues

“…DeLA-Drug allows a fast generation of focused libraries for high-throughput screening without any time-demanding fine-tuning procedure. We used our generative model to generate analogues of compounds targeting the cannabinoid receptor 2 (CB2R), a known target involved in different pathological conditions as cancer and neurodegeneration − and showed, through molecular docking simulations validated ad hoc , its potential as a valuable tool for data-driven generation of potentially active molecules. As the generated molecules are chemically similar to a user-defined query, DeLA-Drug might help medicinal chemists interested in designing analogues of compounds already available in their laboratories and, for this reason, the best candidates for an easy and low-cost synthesis.…”

Screening of potential antidiabetic phytochemicals from Gongronema latifolium leaf against therapeutic targets of type 2 diabetes mellitus: multi-targets drug design

“…Polypharmacology is an exciting approach in drug development and discovery and has gained increased recognition over combinational therapies in the last two decades [19]. Complex diseases such as diabetes require a more modern treatment because they are implicated in several molecular pathways, therefore identifying efficacious small molecules capable of modulating a network of interacting proteins implicated in diabetes with little or no side effect is a legendary magic bullet than the combination of multiple drugs [20].…”

Multi-Target Directed Ligands (MTDLs) Binding the σ1 Receptor as Promising Therapeutics: State of the Art and Perspectives

“…Other proteins may be taken into consideration in the MTDLs development, considering the wide range of σ 1 receptor direct and indirect interactors. Cannabinoid type-2 (CB2) receptors are an example, with recent support from computational methods that point out a partial overlap of the σ 1 and CB2 receptors' pharmacophores [159]. These data strongly suggest the adoption of a merging approach for the development of dual σ 1 /CB2 receptors ligands for a synergistic exploitation of the pathways activated by the two targets in oncology and neurodegenerative diseases.…”