Theoretical studies on the antioxidant potency and mechanism of natural pterocarpans

Abstract

Pterocarpans are fused tetracyclic compounds with benzofuran and benzopyran rings. Some experimental results showed their antioxidant activities, but the relevant mechanism has not been clearly established so far. In this study, we employed the density functional theory (DFT) and molecular docking methods to perform a computational study on the antioxidant activity and mechanism of a series of pterocarpans. Four potential radical-scavenging mechanisms, formal hydrogen atom transfer (fHAT), single electron transfer followed by proton transfer (SET-PT), sequential proton loss electron transfer (SPLET), and sequential proton loss hydrogen atom transfer (SPLHAT) were investigated. The bond dissociation enthalpy (BDE), ionization potential (IP), proton dissociation enthalpy (PDE), proton affinity (PA) and electron transfer enthalpy (ETE) of pterocarpans in gas phase and solvents were calculated. Energy diagram and related transition state structures of the reaction between 6 and hydroperoxyl radical were constructed to further uncover the radical-trapping details. Moreover, the binding potential toward Keap1 was preliminary assessed using molecular docking study, and the possible binding mode was explored. The order of anti-radical ability predicted theoretically in this work is 6 > 7 > 8 > 4 > 5 > 3 > 1 > 2, which is consistent with the existing experimental results. The obtained results show that fHAT is the most favorable mechanism in the gas phase and nonpolar solvents, while in polar media the mixed mechanisms with SPLET and SPLHAT are the most thermodynamically favorable pathway. The studied pterocarpans, particularly 6–8, are proposed to be promising antioxidants with both radical-scavenging and potential Keap1 binding capacity.