In-depth in silico and in vitro screening of selected edible plants for identification of selective C-domain ACE-1 inhibitor and its synergistic effect with captopril

Abstract

Angiotensin converting enzyme (ACE) is a crucial enzyme in renin angiotensin aldosterone system (RAAS), having a pivotal role in blood pressure regulation. Despite its widespread medical applications in hypertension, heart diseases, diabetic nephropathy, and many others, inhibitors of the ACE enzyme suffer from different side effects that limit their use. Plants and natural products are the primary sources of renewable natural compounds that could act as potential leads for different ailments. The following study represents the identification of ACE inhibitors from carefully selected edible plants through adopting combined in silico techniques with biological testing. Molecular docking studies were performed on 1526 phytoconstituents present in 19 edible plants. Biochemical testing of extracts from the top ten hit plants revealed that Moringa oleifera is a potent ACE-1 inhibitor with an IC50 value of 104.4 μg/mL. On top of that, its isolated compound 4-O-caffeoylquinic acid had IC50 value of 62.92 μM. In silico combination analysis showed synergistic effects of moringa extract and 4-O-caffeoylquinic acid combined with captopril, especially at 90% effect level. This, in turn, is likely to reduce side effects and toxicity. Furthermore, selective domain docking showed strong affinity of 4-O-caffeoylquinic acid to the C-domain of ACE enzyme. Since the inflammatory responses and elevated reactive oxygen species in vasculature increase hypertension, the antioxidant effect of the compound was evaluated using 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical scavenging activity and it possessed an acceptable effect with IC50 value of 73.82 μM. These findings advocate the antihypertensive potential of moringa leaves extract. Besides, we introduce 4-O-caffeoylquinic acid as a candidate lead for the design of safe, bidirectional ACE-1 inhibitor with strong antioxidant effect.