Telmisartan is an antihypertensive drug that acts as angiotensin 1 receptor (AT1R) antagonist and a partial peroxisome proliferator activating receptor γ (PPARγ) agonist. Unlike other AT1R antagonists, telmisartan possesses antiproliferative activity, but the exact mechanism is still not completely understood. Therefore, elimination of AT1R antagonistic activity, with retained antiproliferative activity, would provide deeper insight into this mechanism and enable development of antiproliferative drugs without antihypertensive side effect. The aim of this study was to design novel telmisartan derivatives without AT1R antagonistic activity using molecular docking.

Molecular docking analyses were performed in FRED 3.2.0.2 software. Telmisartan was docked into the active site of AT1R (pdb code: 4yay) and key binding interactions were identified: hydrogen bonds with Arg167 and Tyr35, as well as hydrophobic interactions with Tyr92 and Trp84. New derivatives were designed by modification of carboxilic group (amides and esters), in order to alter telmisartan geometry and its AT1R binding properties. Nine derivatives, from which lack of AT1R antagonistic activity could be expected, were selected. The first group showed different interactions and similar binding energies as telmisartan. The second group formed unfavourable interactions with the receptor and possessed significantly higher binding energies than telmisartan.