Density functional theory and enzyme studies support interactions between angiotensin receptor blockers and angiotensin converting enzyme-2: Relevance to coronavirus 2019

• Published in: Bioorganic chemistry 2024-09, Vol.150, p.107602, Article 107602
• Main Authors: Apostolopoulos, Vasso, Georgiou, Nikitas, Tzeli, Demeter, Mavromoustakos, Thomas, Moore, Graham J., Kelaidonis, Konstantinos, Matsoukas, Minos-Timotheos, Tsiodras, Sotirios, Swiderski, Jordan, Kate Gadanec, Laura, Zulli, Anthony, Chasapis, Christos T., Matsoukas, John M.
• Format: Article
• Language: English
• Subjects: Angiotensin Receptor Antagonists - chemistry; Angiotensin Receptor Antagonists - pharmacology; Angiotensin receptor blockers; Angiotensin-Converting Enzyme 2 - chemistry; Angiotensin-Converting Enzyme 2 - metabolism; Angiotensin-Converting Enzyme Inhibitors - chemistry; Angiotensin-Converting Enzyme Inhibitors - metabolism; Angiotensin-Converting Enzyme Inhibitors - pharmacology; Angiotensin-converting enzyme-2; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Benzimidazoles - chemistry; Benzimidazoles - pharmacology; Biphenyl Compounds - chemistry; Biphenyl Compounds - pharmacology; Coronavirus 2019; COVID-19 - virology; COVID-19 Drug Treatment; Density Functional Theory; Humans; Hypertension; Molecular Structure; Proton transfer; SARS-CoV-2 - drug effects; SARS-CoV-2 - enzymology; Severe acute respiratory syndrome coronavirus; Structure-Activity Relationship; Tetrazoles - chemical synthesis; Tetrazoles - chemistry; Tetrazoles - pharmacology
• ISSN: 0045-2068; 1090-2120; 1090-2120
• DOI: 10.1016/j.bioorg.2024.107602

[Display omitted] •Introducing “bisartans, novel sartan-like ARBs•ACC519T has promising antiviral abilities by strongly binding to the centre of ACE2•BV6(K+)2 markedly increases ACE2 activity by decreased AngII and increased Ang(1-7)•Bisartans are appealing COVID-19 treatment due to anti-viral and -hypertensive effects The binding affinities and interactions between eight drug candidates, both commercially available (candesartan; losartan; losartan carboxylic acid; nirmatrelvir; telmisartan) and newly synthesized benzimidazole-N-biphenyltetrazole (ACC519T), benzimidazole bis-N,Nʹ-biphenyltetrazole (ACC519T(2) and 4-butyl-N,N-bis([2-(2H-tetrazol-5-yl)biphenyl-4-yl]) methyl (BV6), and the active site of angiotensin-converting enzyme-2 (ACE2) were evaluated for their potential as inhibitors against SARS-CoV-2 and regulators of ACE2 function through Density Functional Theory methodology and enzyme activity assays, respectively. Notably, telmisartan and ACC519T(2) exhibited pronounced binding affinities, forming strong interactions with ACE2′s active center, favorably accepting proton from the guanidinium group of arginine273. The ordering of candidates by binding affinity and reactivity descriptors, emerged as telmisartan > ACC519T(2) > candesartan > ACC519T > losartan carboxylic acid > BV6 > losartan > nirmatrelvir. Proton transfers among the active center amino acids revealed their interconnectedness, highlighting a chain-like proton transfer involving tyrosine, phenylalanine, and histidine. Furthermore, these candidates revealed their potential antiviral abilities by influencing proton transfer within the ACE2 active site. Furthermore, through an in vitro pharmacological assays we determined that candesartan and the BV6 derivative, 4-butyl-N,N0-bis[20-2Htetrazol-5-yl)bipheyl-4-yl]methyl)imidazolium bromide (BV6(K+)2) also contain the capacity to increase ACE2 functional activity. This comprehensive analysis collectively underscores the promise of these compounds as potential therapeutic agents against SARS-CoV-2 by targeting crucial protein interactions.