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

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dc.catalogadorvdr
dc.contributor.authorSilva, Nicolás Ignacio
dc.contributor.authorSabadini, Gianfranco
dc.contributor.authorCabezas, David
dc.contributor.authorGonzález, Cristofer
dc.contributor.authorGonzález, Paulina
dc.contributor.authorLuo, Jiao
dc.contributor.authorSalas Sánchez, Cristián Osvaldo
dc.contributor.authorMellado, Marco
dc.contributor.authorLorca, Marcos
dc.contributor.authorRomero Parra, Javier
dc.contributor.authorMella, Jaime
dc.date.accessioned2025-10-30T19:33:01Z
dc.date.available2025-10-30T19:33:01Z
dc.date.issued2025
dc.description.abstractTRPC6 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.
dc.fechaingreso.objetodigital2025-10-30
dc.format.extent19 páginas
dc.fuente.origenORCID
dc.identifier.doi10.3390/ph18101577
dc.identifier.eissn1424-8247
dc.identifier.urihttps://doi.org/10.3390/ph18101577
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/106450
dc.information.autorucEscuela de Medicina; Silva, Nicolás Ignacio; S/I; 178249
dc.information.autorucEscuela de Química; Salas Sánchez, Cristián Osvaldo; 0000-0001-7620-2459; 101425
dc.issue.numero10
dc.language.isoen
dc.nota.accesoContenido completo
dc.pagina.final19
dc.pagina.inicio1
dc.revistaPharmaceuticals
dc.rightsacceso abierto
dc.rights.licenseCC BY 4.0 Attribution 4.0 International
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/
dc.subject.ddc500
dc.subject.deweyCienciases_ES
dc.subject.ods03 Good health and well-being
dc.subject.odspa03 Salud y bienestar
dc.titleStructure-guided discovery of benzoic-acid-based TRPC6 ligands. An integrated docking, MD, and MM-GBSA SAR study. Potential therapeutic molecules for autism spectrum disorder
dc.typeartículo
dc.volumen18
sipa.codpersvinculados178249
sipa.codpersvinculados101425
sipa.trazabilidadORCID;2025-10-27
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