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

<b>Background</b>: TRPC6 is recognized as a therapeutically relevant cation channel, whose activation is governed by specific ligand-pocket interactions. <b>Methods</b>: 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. <b>Results</b>: 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. <b>Conclusions</b>: 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.