| Summary: | Hypertension is a worldwide epidemic that has been recognized as the most leading global risks for mortality, with prevalence associated with an increase in systolic blood pressure. high frequency and concomitant risks of cardiovascular and kidney diseases, and major commonality in individuals advanced in age. It is associated with symptoms that include headache, dizziness. shortness of breath, nose bleeds, chest pain. and heart palpitations. Studies on Areca catechu (4. catechu) dwelled heavily on its fruits and was shown to possess angiotensin-converting enzyme (ACE) inhibitory activity. To investigate potential ACE-binding activity in the leaves of A. catechu, in silico molecular docking and toxicity and pharmacokinetic profiling were performed on the compounds found in A. catechu nuts. Streamlined entries from literature search on A. catechu generated I05 compounds, which were subjected to initial toxicity and pharmacokinetic profiling. Following grid optimization of the three C-domain and three N-domain ACE receptor models. molecular docking was performed on the 105 compounds. The top ten A. catechu compounds with comparable ACE binding energies to lisinopril across all six receptor models were subjected to bioisosteric replacement. Only 376 out of 14916 generated analogues met the inclusion criteria for toxicity and pharmacokinetic properties. The 376 analogues were then subjected to molecular docking. and 32 of these analogues possessed ACE binding energies comparable to those of their respective A. catechu compound and standards - benazepril and sampatrilat. The toxicity and pharmacokinetic properties of the top 32 analogues were evaluated. and five analogues - Leuco-DM02-39, Leuco-DM02-66, Leuco-DM05-60/07-09, Querc-DM09 63 and Querc-DMI4-3| were deemed the best.
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