Mechanistic insights into the cofactor binding dynamics and interaction between telmisartan and human thiopurine...

Thiopurine S-methyltransferase (TPMT) is crucial for catalyzing the inactivation and reducing the toxicity of thiopurine class of immunosuppressive drugs which are FDA-approved to treat autoimmune diseases and transplant rejection. Its complete or partial loss of activity during standard-dose thiopurine treatment causes severe bone marrow suppression and death. Therefore, FDA recommends testing TPMT activity to identify patients at high risk of developing life-threatening complications. Here, we tested whether human TPMT is vulnerable to off-target interaction with one of the most commonly prescribed antihypertensive drug telmisartan. The comprehensive molecular modeling in this study shows for the first time that active site of TPMT accommodates telmisartan in a bi-substrate-like binding mode. Consequently, this blocks the co-factor and thiopurine substrate binding subsites in the active site while preserving TPMT's secondary structure. The spatial arrangement and favorable interactions enabled by the interconnected co-factor and thiopurine substrate binding sites causes a stronger binding affinity for telmisartan compared to TPMT's natural co-factors. This study has identified a previously unrecognized mechanism of interaction between TPMT, a biomacromolecule of major importance in thiopurine drug metabolism, and telmisartan, highlighting the necessity for further studies to evaluate adverse interactions of telmisartan with TPMT when co-administered with thiopurine immunosuppressants.