Reverse Docking, Molecular Dynamics Simulation, and Network Analysis Studies to Investigate Potential Antihypertensive Side Effects of Valsartan and Lisinopril
C. Maala, Stephani Joy Y. Macalino, Blessed Isaac Conde, Jamie Bernadette Sy · The Philippine journal of science · 2024
Hypertension, also known as high or raised blood pressure, is a common condition in which the force of circulating blood pushing against the walls of the body’s arteries is excessive. Antihypertensive drugs such as angiotensin II receptor blockers (ARBs) and angiotensin- converting enzyme (ACE) inhibitors, which target different proteins in the same pathway of the renin-angiotensin system, are usually recommended for first-line treatment. Identifying potential off-target proteins and possible side effects correlated with these antihypertensives can help shed light on the potential additional differences of these drugs and yield helpful information for the design and development of future antihypertensives. MAPK8 was identified as a potential off-target protein of valsartan, the chosen representative for ARB, through reverse docking and molecular dynamics. Valsartan exhibited similar binding as the known co- crystallized inhibitor, whereas lisinopril – an ACE inhibitor used for comparison – was unable to form a stable complex with MAPK8. Network analysis further identified E73 and K166 as key residues for valsartan binding while still maintaining the same signaling network as the apo structure. These observations may assist in future studies for the potential polypharmacology of valsartan and for the identification of new indications of already marketed drugs to facilitate drug discovery for other diseases.