Alkamides and Piperamides as Potential Antivirals against the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2)

• Published in: The journal of physical chemistry letters Vol. 11; no. 19; pp. 8008 - 8016
• Main Authors: Gutierrez-Villagomez, Juan Manuel, Campos-García, Tonatiu, Molina-Torres, Jorge, López, Mercedes G, Vázquez-Martínez, Juan
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 01.10.2020
• Subjects: Amides - chemistry; Amides - pharmacology; Amides - therapeutic use; Angiotensin-Converting Enzyme 2; Antiviral Agents - pharmacokinetics; Antiviral Agents - pharmacology; Antiviral Agents - therapeutic use; Benzodioxoles - pharmacokinetics; Benzodioxoles - pharmacology; Benzodioxoles - therapeutic use; Betacoronavirus - drug effects; Coronavirus 3C Proteases; Coronavirus Infections - drug therapy; COVID-19; Cysteine Endopeptidases; Humans; Letter; Models, Molecular; Molecular Docking Simulation; Molecular Dynamics Simulation; Pandemics; Peptidyl-Dipeptidase A - drug effects; Physical Insights into Chemistry, Catalysis, and Interfaces; Piper - chemistry; Piperidines - pharmacokinetics; Piperidines - pharmacology; Piperidines - therapeutic use; Pneumonia, Viral - drug therapy; SARS-CoV-2; Viral Nonstructural Proteins - antagonists & inhibitors
• ISSN: 1948-7185; 1948-7185
• DOI: 10.1021/acs.jpclett.0c01685

The pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has quickly spread globally, infecting millions and killing hundreds of thousands of people. Herein, to identify potential antiviral agents, 97 natural amide-like compounds known as alkamides and piperamides were tested against SARS-CoV-2 main protease (Mpro) and RNA-dependent RNA polymerase (RdRp), and the human angiotensin-converting enzyme 2 (ACE2) using molecular docking and molecular dynamics simulations. The docking results showed that alkamides and dimeric piperamides from Piper species have a high binding affinity and potential antiviral activity against SARS-CoV-2. The absorption, distribution, metabolism, and excretion (ADME) profile and Lipinski’s rule of five showed that dimeric piperamides have druglikeness potential. The molecular dynamics results showed that pipercyclobutanamide B forms a complex with Mpro at a similar level of stability than N3-I. Our overall results indicate that alkamides and piperamides, and specifically pipercyclobutanamide B, should be further studied as compounds with SARS-CoV-2 antiviral properties.