Biology subjects

Castano, J. D.

Publications and source records attributed to Castano, J. D..

3 recordsLinked to original sources

bioRxiv2026

Structural conservation of the gabapentinoid binding site in human and Caenorhabditis elegans α2δ subunits: a docking and molecular dynamics perspective

Pain is a global health burden, highlighting the need for effective therapeutic strategies. Gabapentin (GBP) and pregabalin (PGB), used for neuropathic pain, act primarily through 2{delta} auxiliary subunits of voltage-gated calcium channels. Caenorhabditis elegans expresses UNC-36, an ortholog of mammalian 2{delta} proteins involved in calcium-channel function and nocifensive behavior. However, whether UNC-36 preserves the molecular features required for gabapentinoid recognition remains unclear. We compared human 2{delta}-1 and UNC-36 using sequence and structural analyses, molecular docking, 500-ns molecular dynamics simulations, interaction profiling, principal component and free-energy landscape analyses, and MM/GBSA calculations. UNC-36 preserved the overall architecture of the mammalian gabapentinoid-binding region despite substantial sequence divergence, and both ligands remained associated with the modeled pockets. However, residue-level interaction networks differed between species. Human 2{delta}-1 showed greater contributions from aromatic interactions, whereas UNC-36 relied more prominently on cationic and hydrogen-bond donor interactions mediated by Arg501 and Arg503. The human 2{delta}-1-PGB complex maintained the most stable ligand pose, whereas 2{delta}-1-GBP showed greater positional variation. In UNC-36, PGB exhibited greater deviation from its initial binding pose than GBP. The first two principal components accounted for more conformational variance in UNC-36 complexes than in human complexes. MM/GBSA estimates showed that PGB was energetically favored over GBP in human 2{delta}-1, whereas GBP was favored over PGB in UNC-36. These findings show that conservation of the gabapentinoid-binding architecture is accompanied by species-specific differences in interaction chemistry, conformational dynamics, and estimated binding energetics, providing a molecular basis for interpreting C. elegans gabapentinoid responses in a translational context.

molecular biology↗

bioRxiv2025

Terpenes as Modulators of Nociceptive Signaling: Behavioral and Molecular Insights from Caenorhabditis elegans

Terpenes such as Limonene and {beta}-Caryophyllene have demonstrated pain-modulating properties, potentially through interactions with TRPV1 receptors. This study examines the antinociceptive effects of four terpenes derived from Cannabis sativa: Limonene, {beta}-Caryophyllene, -Humulene, and -Myrcene using Caenorhabditis elegans (C. elegans). The primary objective was to characterize terpene-induced modulation of nocifensive responses to noxious heat, and to elucidate their influence on molecular pathways via specific receptor targets. Thermotaxis assays quantified the antinociceptive activity of increasing terpene concentrations in wild-type nematodes. To assess receptor-specific mechanisms, assays were performed in mutant strains lacking functional OCR-2 and OSM-9 (TRPV-like vanilloid nociceptors), and NPR-19 and NPR-32 (encoding cannabinoid-like receptors). Proteomic profiling coupled with bioinformatics analysis identified terpene-induced alterations in signaling pathways and biological processes. All four terpenes exhibited significant antinociceptive activity in wild-type C. elegans, with impaired effects observed in vanilloid receptor mutants, implicating TRPV-like channels in their mechanism of action. Proteomic and pathway analyses revealed terpene-specific molecular signatures, highlighting differential modulation of neuronal and stress-responsive signaling cascades. By elucidating the molecular mechanisms underlying terpene-induced nociceptive modulation, this work strengthens the growing body of evidence supporting the therapeutic promise of terpenes in pain management outside the effect referred to as the "entourage effect."

pharmacology and toxicology↗

bioRxiv2025

Cannabivarin and Tetrahydrocannabivarin Modulate Nociception via Vanilloid Channels and Cannabinoid-Like Receptors in Caenorhabditis elegans

Cannabis has attracted growing interest for its therapeutic potential, especially in pain management. This study explores the antinociceptive effects of two promising non-psychoactive cannabinoids, cannabivarin (CBV) and tetrahydrocannabivarin (THCV), using Caenorhabditis elegans (C. elegans), a nematode model that expresses homologs of mammalian cannabinoid and vanilloid receptors. Thermotaxis assays were employed to quantify the antinociceptive effects of CBV and THCV in C. elegans. Wild-type animals were exposed to increasing concentrations of each compound to establish dose-response relationships. To investigate potential molecular targets, additional experiments were performed using mutant strains deficient in vanilloid receptor homologs (OCR-2 and OSM-9) and cannabinoid receptor homologs (NPR-19 and NPR-32). Mass spectrometry-based proteomics combined with network biology analyses were used to identify the biological pathways associated with drug response. Results confirmed that both compounds elicit dose-dependent antinociceptive effects. Mutant analyses support the involvement of vanilloid and cannabinoid signaling pathways in mediating these responses. These findings highlight the potential of CBV and THCV as non-psychoactive analgesic agents and support further research into their mechanisms of action and translational relevance for mammalian pain management.

pharmacology and toxicology↗