Natural chlocarbazomycins as potential adenosine A1 receptor antagonists: ligand-based and structure-based virtual screening, quantum chemical analysis and CNS MPO study

Abstract Parkinson’s disease (PD) is a neurodegenerative disorder that causes irreversible damage to brain structures through neurotransmitter oxidation, leading to motor symptoms like tremors and muscle rigidity. Although existing therapies target monoamine oxidase B, recent research has highlighted​​ a correlation between adenosine A 1 and A 2A R receptors in inhibiting dopamine reuptake, as observed in rats. Chlocarbazomycins (CCB), carbazole derivatives with neuroprotective properties, show potential for central nervous system (CNS) therapies. This study examines the structural and bioactivity properties of four carbazomicin derivatives (CCB1-4) using quantum-level Density Functional Theory (DFT) calculations, virtual screening, and a predictive pharmacokinetics study. The results showed that different environments (water, DMSO, and chloroform) had minimal impact on the reactivity of CCB1-4 derivatives. Structure-based virtual screening revealed that the heteroaromatic nature of CCB1-4 closely resembles that of adenosine (ADN), the endogenous ligand for A 1 R receptors. Molecular docking showed that CCB3 had the highest affinity for the receptor, with a binding energy of − 8.6 kcal/mol at the ADN agonist site. Molecular dynamics simulations confirmed the stable binding of CCB3, with a free energy of − 25.9 kcal/mol, suggesting that CCB3 may act as an antagonist to ADN in A1R modulation. The results of predictive pharmacokinetic studies indicate that the compound exhibits high passive cell permeability ( P app, A→B > 10 × 10 − 6 cm/s) and low hepatic clearance, which collectively ensure the safe activity of the compound in the CNS. These findings suggest that CCB3 has potential in PD treatment.