Structure-based virtual screening methods for the identification of novel phytochemical inhibitors targeting furin protease for the management of COVID-19

• Published in: Frontiers in cellular and infection microbiology 2024, Vol.14, p.1391288
• Main Authors: Kumar Tiwari, Prashant, Chouhan, Mandeep, Mishra, Richa, Gupta, Saurabh, Chaudhary, Anis Ahmad, Al-Zharani, Mohammed, Ahmed Qurtam, Ashraf, Nasr, Fahd A, Jha, Niraj Kumar, Pant, Kumud, Kumar, Mukesh, Kumar, Sanjay
• Format: Article
• Language: English
• Subjects: Antiviral Agents - chemistry; Antiviral Agents - pharmacology; COVID-19 - virology; COVID-19 Drug Treatment; Furin - antagonists & inhibitors; Furin - metabolism; furin protein; Humans; Molecular Docking Simulation; molecular dynamics (MD) simulation; phytochemical inhibitors; Phytochemicals - chemistry; Phytochemicals - pharmacology; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Protein Binding; SARS-CoV-2; SARS-CoV-2 - drug effects; SARS-CoV-2 - enzymology; Spike Glycoprotein, Coronavirus - antagonists & inhibitors; Spike Glycoprotein, Coronavirus - chemistry; Spike Glycoprotein, Coronavirus - metabolism; virtual screening
• ISSN: 2235-2988; 2235-2988
• DOI: 10.3389/fcimb.2024.1391288

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus, is a highly contagious respiratory disease with widespread societal impact. The symptoms range from cough, fever, and pneumonia to complications affecting various organs, including the heart, kidneys, and nervous system. Despite various ongoing efforts, no effective drug has been developed to stop the spread of the virus. Although various types of medications used to treat bacterial and viral diseases have previously been employed to treat COVID-19 patients, their side effects have also been observed. The way SARS-CoV-2 infects the human body is very specific, as its spike protein plays an important role. The S subunit of virus spike protein cleaved by human proteases, such as furin protein, is an initial and important step for its internalization into a human host. Keeping this context, we attempted to inhibit the furin using phytochemicals that could produce minimal side effects. For this, we screened 408 natural phytochemicals from various plants having antiviral properties, against furin protein, and molecular docking and dynamics simulations were performed. Based on the binding score, the top three compounds (robustaflavone, withanolide, and amentoflavone) were selected for further validation. MM/GBSA energy calculations revealed that withanolide has the lowest binding energy of -57.2 kcal/mol followed by robustaflavone and amentoflavone with a binding energy of -45.2 kcal/mol and -39.68 kcal/mol, respectively. Additionally, ADME analysis showed drug-like properties for these three lead compounds. Hence, these natural compounds robustaflavone, withanolide, and amentoflavone, may have therapeutic potential for the management of SARS-CoV-2 by targeting furin.