Targeting Age-Associated NAD⁺ Decline: in silico Evaluation of Minocycline as an Inhibitor of CD38 and PARP2

Abstract

<title>Abstract</title> Chronic activation of enzymes that require NAD⁺ for their activity such as CD38 and PARPs accelerates its decline with age, impairing cellular metabolism and contributing to degenerative processes. Targeting these enzymes may help preserve NAD⁺ levels and delay ageing-related pathologies. This study investigated the potential inhibitory activity of minocycline against CD38 and PARP2 using <italic>in silico</italic> approaches. Structures of minocycline and standard inhibitors for CD38 and PARPs were obtained from PubChem, while protein structures were retrieved from the Protein Data Bank (PDB). The ligands were docked against the protein using PyRx, and ligand-protein interactions were visualized with Discovery Studio Visualizer. Pharmacokinetic properties were assessed via pkCSM, toxicity was predicted using ProTox, and membrane permeability evaluated using PerMM. Ligands with favourable docking scores were further subjected to molecular dynamics (MD) simulations over a 100 ns trajectory. Minocycline demonstrated higher binding affinity for CD38 (− 8.9 kcal/mol) and PARP2 (− 10.2 kcal/mol) compared to their respective standard inhibitors (− 8.4 and − 10.1 kcal/mol). MD simulations revealed that minocycline formed more stable complexes with both targets, as indicated by lower root mean square deviation (RMSD) and root mean square fluctuation (RMSF) values. Radius of gyration analysis confirmed compact and stable protein-ligand complexes. These results suggest that minocycline may inhibit NAD⁺ consumers more effectively than existing inhibitors, potentially preserving NAD⁺ levels and mitigating the ageing process. The findings support the rationale for repurposing minocycline as a multi-target anti-ageing therapeutic.