Computational Prioritization of gC1qR Binding Candidates at the C1q Interaction Surface

ABSTRACT

Cancer cells evade complement‐mediated immune clearance by secreting the receptor gC1qR, which binds C1q and inhibits classical pathway activation. Disrupting the C1q‐gC1qR interaction offers a novel immunotherapeutic strategy to restore antitumor immunity. Here, we conducted an in silico study to characterize the C1q‐gC1qR interface and identify small‐molecule candidates. Protein‐protein docking and MM/GBSA calculations revealed hydrogen bonds and identified Lys173 and Lys200 on C1q as critical hotspot residues, with a binding free energy of −107.79 kcal/mol. Pharmacophore models were generated using ZINCPharmer, screening 3465 ligands from the ZINC database. A 2D‐QSAR model was established using PaDEL descriptors and multiple linear regression on a dataset of 123 ligands, divided into a training set ( n = 86, R ² = 0.886) and a test set ( n = 37, R ² = 0.837) for prediction. Re‐docking with AutoDock Vina prioritized two compounds, ZINC95486185 and ZINC95486376, exhibiting binding affinities of −8.98 ± 0.4 kcal/mol and −8.90 ± 0.06 kcal/mol, respectively. PLIP analysis demonstrated hydrophobic interactions with gC1qR residues Ala81, Phe82, Phe85, and Asp88. ADMET profiling indicated pharmacokinetics, non‐mutagenicity, and low solubility, suggesting parenteral administration. 100‐ns molecular dynamics simulations demonstrated the structural stability of ZINC95486376, highlighting it as a promising candidate for restoring complement‐dependent antitumor immunity.