Ketone Body Scaffolds and SIRT1 Activators as PPAR-δ Ligands: A Structure-Based Virtual Screening Study in the Context of Intestinal Stem Cell Biology

Background. PPAR-δ couples fatty acid signalling to intestinal stem cell (ISC) proliferation and metabolic adaptation. Fasting and ketogenic feeding both activate PPAR-δ in ISCs, but whether endogenous ketone bodies engage the receptor directly — in addition to their established HDAC-inhibitory mechanism — is not known. Methods. We screened a 23-compound library against three crystallographic structures of the PPAR-δ ligand-binding domain (PDB 3TKM, 2ZNP, 2GTK). The library covered endogenous keto metabolites, SIRT1 activators, natural fatty acid PPAR-δ ligands, and designed acetoacetate-derived scaffolds. Docking used AutoDock Vina 1.2.7. Candidates were filtered by Lipinski, Veber and PAINS criteria and profiled for ADMET. Protocol specificity was poor (AUC 0.335, below the chance level of 0.5), so all conclusions are hypothesis-generating. Results. GW501516 (− 10.69 kcal/mol) and DHA (− 7.90 kcal/mol) reproduced their expected rank order. Endogenous ketone bodies bound weakly but consistently across all three receptor conformations (− 3.8 to − 4.4 kcal/mol), compatible with allosteric sensitisation. SIRT1 activators scored substantially higher than annotated (SRT1720 − 8.62; resveratrol − 7.67 kcal/mol), consistent with direct LBD engagement in parallel with SIRT1-mediated coactivation. Among designed scaffolds, AcAc_biphenyl_001 (MW 253 Da, QED 0.850, LE 0.49 kcal/mol per heavy atom) scored − 9.31 kcal/mol and passed every bioavailability filter. Conclusions. To our knowledge, this is the first systematic computational characterisation of PPAR-δ engagement by ketone body scaffolds. The data support an allosteric sensitiser model for BHB and acetoacetate, are consistent with a direct PPAR-δ ligand component for SIRT1 activators, and identify AcAc_biphenyl_001 as a drug-like lead warranting ISC organoid and reporter gene validation.