Atomistic Modeling of Triplet-Triplet Energy-Transfer Rates from Drug (S)-Propranolol to (R)-Cinacalcet in Human α1-Acid Glycoprotein

Triplet-triplet energy transfer (TTET) is one of the potential approaches to detect drug-drug interactions in protein environments. Here, quantum mechanism/molecular mechanics (QM/MM), molecular dynamics (MD), and rate theories are employed to quantitatively predict the TTET rates from a drug (S)-propranolol (PPN) to (R)-cinacalcet (CIN) within the cavity of human alpha(1)-acid glycoprotein. The results indicate that the TTET rates from the PPN to CIN can be described by a Marcus-type theory for electron transfer. As the drugs are set into the protein cavity, the total reorganization energy is enhanced from 0.796 to 0.870 eV, and the thermal motions of drugs and protein cause dramatic electronic coupling fluctuations. However, the fluctuation effect on TTET rates can be efficiently considered by a thermally averaged electronic coupling, which is confirmed by the rate calculations obviously incorporating the non-Condon effect. Furthermore, Fermis golden rule predicts the consistent TTET rates with experimental ones, demonstrating the importance of nuclear tunneling effect.