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

Prashant Kumar Tiwari; Mandeep Chouhan; Richa Mishra; Saurabh Gupta; Anis Ahmad Chaudhary; Mohammed Al-Zharani; Ashraf Ahmed Qurtam; Fahd A Nasr; Niraj Kumar Jha; Kumud Pant; Mukesh Kumar; Sanjay Kumar

doi:10.3389/fcimb.2024.1391288

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

Front Cell Infect Microbiol. 2024 Jun 11:14:1391288. doi: 10.3389/fcimb.2024.1391288. eCollection 2024.

Authors

Affiliations

¹ Biological and Bio-computational Lab, Department of Life Sciences, Sharda School of Basic Sciences and Research, Sharda University, Greater Noida, Uttar Pradesh, India.
² Department of Computer Engineering, Parul University, Gujarat, India.
³ Department of Biotechnology, GLA University, Mathura, Uttar Pradesh, India.
⁴ Department of Biology, College of Science, Imam Mohammad Ibn Saud Islamic University (IMSIU), Riyadh, Saudi Arabia.
⁵ Centre for Global Health Research, Saveetha Medical College, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, India.
⁶ School of Bioengineering & Biosciences, Lovely Professional University, Phagwara, India.
⁷ Department of Biotechnology, Sharda School of Engineering and Technology, Sharda University, Greater Noida, Uttar Pradesh, India.
⁸ Department of Biotechnology, Graphic Era Deemed to Be University, Dehradun, Uttarakhand, India.
⁹ Department of Biophysics, All India Institute of Medical Sciences, New Delhi, India.

Abstract

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.

Keywords: SARS-CoV-2; furin protein; molecular dynamics (MD) simulation; phytochemical inhibitors; virtual screening.

MeSH terms

Antiviral Agents* / chemistry
Antiviral Agents* / pharmacology
COVID-19 / virology
COVID-19 Drug Treatment*
Furin* / antagonists & inhibitors
Furin* / metabolism
Humans
Molecular Docking Simulation*
Phytochemicals* / chemistry
Phytochemicals* / pharmacology
Protease Inhibitors / chemistry
Protease Inhibitors / pharmacology
Protein Binding
SARS-CoV-2* / drug effects
SARS-CoV-2* / enzymology
Spike Glycoprotein, Coronavirus / antagonists & inhibitors
Spike Glycoprotein, Coronavirus / chemistry
Spike Glycoprotein, Coronavirus / metabolism

Substances

Furin
Phytochemicals
Antiviral Agents
Protease Inhibitors
Spike Glycoprotein, Coronavirus
FURIN protein, human
spike protein, SARS-CoV-2

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported and funded by the Deanship of Scientific Research at Imam Mohammad Ibn Saud Islamic University (IMSIU) (grant number IMSIU-RPP2023022).