Screening and toxicity evaluation of natural compounds as adenosine 2a and 2b receptor ligands: insights from molecular docking, dynamics, and ADMET analysis

Recent studies suggest that immunological and inflammatory responses in cardiovascular disorders, such as hypertension, myocardial infarction, ischemia injury, heart failure, arrhythmias, and atherosclerosis, may be affected by changes in the adenosine system. Pharmacological modulation of adenosine occurs through its receptor subtypes. In numerous preclinical studies, the activation of adenosine receptor 2A (A_2AR) or the blockade of adenosine receptor 2B (A_2BR) has shown promising results against cardiovascular diseases. This <i>in silico</i> study aimed to identify potential natural compounds that can activate A_2AR or block A_2BR without causing toxicity. Natural compounds were screened using COlleCtion of Open Natural ProdUcTs (COCONUT) or Natural Product Activity and Species Source Database (NPASS) databases to find agonists for A_2AR or an antagonists/inverse agonists for A_2BR. These compounds were then pre-filtered based on their toxicity profiles. The remaining compounds were subjected to molecular docking against A_2AR and A_2BR followed by molecular dynamics simulations were conducted. Finally, selected compounds' ADMET properties were determined using ADMETlab 2.0 web tool. Ultimately, one novel natural compound with potential agonistic activity (COCONUT IDs: CNP0450901) for A_2AR and one antagonist/inverse agonist (rauwolscine) for A_2BR were identified.