Discovery of Novel Multi-target Inhibitor of angiotensin type 1 receptor and neprilysin inhibitors from Traditional Chinese Medicine

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.

Multi-Target In-Silico modeling strategies to discover novel angiotensin converting enzyme and neprilysin dual inhibitors

“…The large size and shape of the binding site pose challenges for molecular docking on targets. In cACE and NEP molecular docking calculations, constraints are applied to obtain reliable orientations of ligands, including hydrogen bonds with His353 and/or His513 (cACE) and His711 (NEP) along with metal-chelator interactions 43 , 80 . The study found that native ligands in protein structure are maximally superimposed with co-crystallized ligands, confirming the docking protocol's agreement with previous work and confirming the interaction of native ligands(Fig.…”

“…Recent advancements in the pharmaceutical industry, such as the development of a Losartan and metabolite co-drug with NEP inhibitors, demonstrate innovative approaches in drug discovery 41 . The discovery of orally active TD-0212 and Gyrophoric acid further emphasizes the necessity of dual AT1/NEP inhibition with potentially lower angioedema risk 42 , 43 . Omapatrilat and LCZ696 (Entresto®) are molecules discovered to target the renin–angiotensin–aldosterone system and neprilysin together 44 – 47 .…”

Lichen Depsides and Tridepsides: Progress in Pharmacological Approaches

“…Gyrophoric acid has been shown to have antihypertensive properties by acting as an angiotensin II type-1 receptor (AT1) antagonist by interacting with residues ARG167, TRP84, and VAL108 [ 123 ]. Moreover, gyrophoric acid has been identified as a non-competitive PTP1B inhibitor, with an IC 50 value of 3.6 μM, making it a drug candidate for type 2 diabetes and obesity [ 99 ].…”

Tridepsides as potential bioactives: a review on their chemistry and the global distribution of their lichenic and non-lichenic natural sources

“…Other potential therapeutic effects of GA include cardiovascular action as a direct angiotensin II type-1 receptor antagonist (IC 50 of 29.76 µM) ( Huo et al., 2019 ), DNA interaction as a potential DNA-binding compound ( Plsíkova et al., 2014 ), and anti-diabetic activity through antiglycation and anti-urease activity ( Seo et al., 2009 ; Choudhary et al., 2011 ). There is also evidence that TE, the di-methylated analog of GA, may prevent Alzheimer’s disease.…”