Losartan as an ACE inhibitor: a description of the mechanism of action through quantum biochemistry

• Published in: RSC advances Vol. 12; no. 44; pp. 28395 - 2844
• Main Authors: Bezerra, Eveline M, de Alvarenga, Érika C, dos Santos, Ricardo P, de Sousa, Jeanlex S, Fulco, Umberto L, Freire, Valder N, Albuquerque, Eudenilson L, da Costa, Roner F
• Format: Journal Article
• Language: English
• Published: Cambridge Royal Society of Chemistry 05.10.2022; The Royal Society of Chemistry
• Subjects: Biochemistry; Chemistry; Crystallography; Hypertension
• ISSN: 2046-2069; 2046-2069
• DOI: 10.1039/d2ra04340h

Losartan (LST) is a potent and selective angiotensin II (Ang II) type 1 (AT1) receptor antagonist widely used in the treatment of hypertension. The formation of Ang II is catalyzed by the angiotensin I-converting enzyme (ACE) through proteolytic cleavage of angiotensin I (Ang I), which is involved in the control of blood pressure. Despite the vast literature on the relationship of losartan with the renin-angiotensin system (RAS), the actions of losartan on the sACE enzyme are so far poorly understood. In view of this, we investigated how losartan can interact with the sACE enzyme to block its activity and intracellular signaling. After performing docking assays following quantum biochemistry calculations using losartan and sACE crystallographic data, we report that their interaction results reveal a new mechanism of action with important implications for understanding its effects on hypertension. Projection of the interaction energy with ligands lisinopril (LPR) and losartan (LST) for each amino acid of the somatic angiotensin converting enzyme (sACE) mapped onto the molecular surface, according to the scale bar.