Browsing by Author "Romero Parra, Javier"

Now showing 1 - 2 of 2
  • Thumbnail Image
    Item
    Structure-guided discovery of benzoic-acid-based TRPC6 ligands. An integrated docking, MD, and MM-GBSA SAR study. Potential therapeutic molecules for autism spectrum disorder
    (2025) Silva, Nicolás Ignacio; Sabadini, Gianfranco; Cabezas, David; González, Cristofer; González, Paulina; Luo, Jiao; Salas Sánchez, Cristián Osvaldo; Mellado, Marco; Lorca, Marcos; Romero Parra, Javier; Mella, Jaime
    TRPC6 is recognized as a therapeutically relevant cation channel, whose activation is governed by specific ligand–pocket interactions. Methods: An integrated in silico workflow was employed, comprising structure-based docking, 100-nanosecond molecular dynamics (MD) simulations, and MM-GBSA calculations. Benzoic-acid–based compounds were designed and prioritized for binding to the TRPC6 pocket, using a known literature agonist as a reference for benchmarking. Results: Within the compound series, BT11 was found to exhibit a representative interaction profile, characterized by a key hydrogen bond with Trp680 (~64% occupancy), persistent salt-bridge interactions with Lys676 and Lys698, and π–π stacking with Phe675 and Phe679. A favorable docking score (−11.45 kcal/mol) was obtained for BT11, along with a lower complex RMSD during MD simulations (0.6–4.8 Å), compared with the reference compound (0.8–7.2 Å). A reduction in solvent-accessible surface area (SASA) after ~60 ns was also observed, suggesting decreased water penetration. The most favorable binding energy was predicted for BT11 by MM-GBSA (−67.72 kcal/mol), while SOH95 also ranked highly and slightly outperformed the reference. Conclusions: These convergent computational analyses support the identification of benzoic-acid–derived chemotypes as potential TRPC6 ligands. Testable hypotheses are proposed, along with structure–activity relationship (SAR) guidelines, to inform experimental validation and guide the design of next-generation analogs.
  • Thumbnail Image
    Item
    Synthesis of Novel Chloro-Benzo [d]imidazole Regioisomers as Selective CB2 Receptor Agonists: Indirect Functional Evaluation and Molecular Insights
    (2025) Zuñiga Salazar, Valeria; Burgos Ravanal, Renato; Soto Flores, Jonathan; Sabadini, Gianfranco; González, José Vicente; Mella, Jaime; Romero Parra, Javier
    The cannabinoid type 2 receptor (CB2 receptor) has been extensively studied in recent years due to the benefits associated with its modulation, including the regulation of the inflammatory response, neuroimmunomodulatory properties, and antitumor effects, all with the advantage of lacking significant psychoactive effects. Herein, we report the design, synthesis, characterization, biological assays, and molecular modelling analyses of novel (5/6-chloro-2-aryl-1H-benzo [d]imidazol-1-yl)(4-methoxyphenyl)methanone and 5/6-chloro-1-(4-methoxybenzyl)-2-aryl-1H-benzo [d]imidazole regioisomers as potential cannabinoid type 2 receptor ligands. Methods: The compounds were evaluated for their presumed CB2 agonist activity using an indirect receptor-dependent apoptotic cell death assay exerted by cannabinoids, using the cell lines HEK293 (low CB1/CB2 expression), U-87 MG (high CB1 expression), and HL-60 (exclusive CB2 expression), and including the known cannabinoid ligands WIN-55,212-2 and AM630 as reference ligands. Flow cytometry was performed to assess apoptosis. Molecular docking and molecular dynamics simulations were used to explore ligand-receptor interactions at the CB2 active site. Results: Compounds 3a, 3b’, 3c, and 4b selectively reduced HL-60 cell viability, similar to WIN-55,212-2, while showing no toxicity toward HEK293 or U-87 MG cells. Flow cytometry indicated that compounds 3a and 3c induced apoptosis in HL-60 cells comparable to WIN-55,212-2. Computational studies suggested that both compounds bind within the CB2 receptor active site predominantly through π–π and hydrophobic interactions involving their benzo [d]imidazole cores, 2-aryl moieties, and 4-methoxybenzoyl scaffolds, resembling the binding patterns of established CB2 ligands. Conclusions: Compounds 3a and 3c exert selective cytotoxicity against HL-60 cells, likely via a CB2 agonist-mediated apoptotic mechanism. The applied combined experimental and computational approach provides a rapid, informative strategy for preliminary evaluation of CB2 ligands and guides subsequent detailed pharmacological studies.