Abstract
Angiotensin II type-1 receptor–neprilysin inhibitor (ARNi) is consisted of Angiotensin II type-1 receptor (AT1) antagonist and neprilysin (NEP) inhibitor, which could simultaneously increase the vasodilators of the natriuretic peptides and antagonize vasoconstrictors of Ang II. ARNi has been proved a superior effect and lower risks of death on chronic heart failure (CHF) and hypertension. In this paper, ARNi from Traditional Chinese Medicines (TCM) was discovered based on target combination of AT1 and NEP by virtual screening, biological assay and molecular dynamics (MD) simulations. Two customized strategies of combinatorial virtual screening were implemented to discover AT1 antagonist and NEP inhibitor based on pharmacophore modeling and docking computation respectively. Gyrophoric acid (PubChem CID: 135728) from Parmelia saxatilis was selected as AT1 antagonist and assayed with IC50 of 29.76 μM by calcium influx assay. And 3,5,3′-triiodothyronine (PubChem CID: 861) from Bos taurus domesticus was screened as NEP inhibitor and has a dose dependent inhibitory activity by biochemistry fluorescence assay. Combined with MD simulations, these compounds can generate interaction with the target, key interactive residues of ARG167, TRP84, and VAL108 in AT1, and HIS711 in NEP were also identified respectively. This study designs the combinatorial strategy to discover novel frames of ARNi from TCM, and gyrophoric acid and 3,5,3′-triiodothyronine could provide the clues and revelations of drug design and therapeutic method of CHF and hypertension for TCM clinical applications.
Highlights
Chronic heart failure (CHF) is the progressive inability of the heart to supply inadequate blood flow to vital organs
Target combination of angiotensin II receptor type 1 (AT1) and NEP is critical for treating chronic heart failure (CHF) and hypertension, angiotensin type receptor-neprilysin inhibitors (ARNi) has never been discovered from Traditional Chinese Medicine (TCM)
Hit compounds obtained by pharmacophore were docked into docking model of AT1 antagonists, and top 10 compounds were retained as potential candidates
Summary
Chronic heart failure (CHF) is the progressive inability of the heart to supply inadequate blood flow to vital organs. LCZ696, consisted of neprilysin (NEP) inhibitors (sacubitril, PubChem CID:9811834) and angiotensin II receptor type 1 (AT1) antagonists (valsartan), is developed to treat CHF and hypertension[7]. Further development of angiotensin type 1 receptor-neprilysin inhibitors (ARNi) is essential to treat CHF with fewer side effects. Target combination of AT1 and NEP is critical for treating CHF and hypertension, ARNi has never been discovered from TCM. Two screening processes of NEP inhibitors and AT1 antagonists were implemented to discover potential TCM ARNi. Molecular dynamics simulation was further utilized to prove the interaction of TCM ARNi. biological assays were utilized to identify the interaction of targets and ARNi. This study provided the novel framework of efficient screening of ARNi leading compounds from TCM for further drug design and development. The TCM combination of ARNi was beneficial discovery of original ARNi of TCM for treating CHF and hypertension
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