Ragazzi, E. | Search bioRxiv

bioRxiv2026

Deciphering the Caffeine-Specific Neuroprotective Axis: Comparative Docking and Pharmacokinetic Evaluation of the Coffee Phytocomplex

BackgroundEpidemiological studies consistently report inverse associations between caffeinated coffee consumption and dementia risk. However, the molecular mechanisms linking coffee-derived phytochemicals to neuroprotection remain only partially understood. ObjectiveTo evaluate, through integrated in silico pharmacology, the relative contribution of adenosine receptor modulation versus direct amyloidogenic enzyme and kinase inhibition in mediating the putative neuroprotective effects of major coffee constituents. MethodsMolecular docking analyses were conducted for caffeine, paraxanthine, chlorogenic acid, trigonelline, cafestol, and kahweol against adenosine A2A and A1 receptors (A2AR, A1R), {beta}-secretase 1 (BACE1), glycogen synthase kinase-3{beta} (GSK-3{beta}), and NLRP3 inflammasome components. Docking was performed using the CB-Dock2 platform. Binding affinities, interaction patterns, and ligand efficiency metrics were assessed. Blood-brain barrier permeability and ADMET properties were predicted using pkCSM. ResultsCaffeine and paraxanthine demonstrated structurally coherent binding within the orthosteric pockets of A2AR and A1R, supported by favorable predicted blood-brain barrier penetration and high unbound fractions. Ligand efficiency analysis identified adenosine receptors as the most pharmacologically plausible targets for small xanthine derivatives. Although larger phytochemicals exhibited stronger absolute docking scores at BACE1, GSK-3{beta}, and NLRP3, predicted pharmacokinetic constraints suggest a small biological effect due to a limited central exposure. ConclusionsThese findings support an adenosine receptor-centered mechanism as the dominant molecular axis linking caffeinated coffee consumption to reduced dementia risk, favoring neuroinflammatory and signaling modulation over direct enzymatic inhibition. Experimental validation is warranted to confirm translational relevance. GRAPHICAL ABSTRACT O_FIG O_LINKSMALLFIG WIDTH=193 HEIGHT=200 SRC="FIGDIR/small/723029v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@18e50f8org.highwire.dtl.DTLVardef@65f39corg.highwire.dtl.DTLVardef@15cb314org.highwire.dtl.DTLVardef@f1068b_HPS_FORMAT_FIGEXP M_FIG C_FIG

pharmacology and toxicology↗

bioRxiv2025

Postural test to differentiate primary aldosteronism from low-renin hypertension

BackgroundThe diagnostic accuracy of screening and confirmatory tests to differentiate primary aldosteronism (PA) among patients with low-renin hypertension (HTN) is suboptimal. We aimed to assess the role of postural stimulation test (PST, previously used for PA subtyping) in differentiating PA from low-renin HTN. Patients and methodsClinical and endocrine data in clinostatic position (CP) and orthostatic position (OP) during PST were evaluated in 190 hypertensive patients: 80 PA and 110 low-renin HTN. Multivariate techniques were computed: Principal Component Analysis (PCA), Partial Least Square-Discriminant Analysis (PLS-DA) and k-means clustering. ResultsPST response differentiated our cohort: 96% of PA were detected in the 56/190 patients with always suppressed renin levels, 80% of patients with low-renin HTN were identified among 56/190 subjects with de-suppression of renin from CP to OP and 78/190 with always measurable renin. Increased potassium and measurable renin in OP were predictors of low-renin HTN. Cluster analysis distinguished PA from low-renin HTN: Cluster 2 included 104/110 low-renin HTN; Cluster 1 PA patients showed a higher frequency of suppressed renin levels at baseline and during PST (100% in CP and 95% in OP, respectively). Cluster 1 low-renin HTN patients had lower potassium and a higher frequency of suppressed renin levels at diagnosis and during PST, compared to Cluster 2. PLS-DA and PCA confirmed that renin in OP, renin response to PST and presence of hypokalemia were the most relevant parameters for distinguishing PA from low-renin HTN. ConclusionRenin response during PST can be used to differentiate PA from low-renin HTN.

physiology↗