Computational and network pharmacology analysis of bioflavonoids as possible natural antiviral compounds in COVID-19

Rajesh Patil; Rupesh Chikhale; Pukar Khanal; Nilambari Gurav; Muniappan Ayyanar; Saurabh Sinha; Satyendra Prasad; Yadu Nandan Dey; Manish Wanjari; Shailendra S Gurav

doi:10.1016/j.imu.2020.100504

Computational and network pharmacology analysis of bioflavonoids as possible natural antiviral compounds in COVID-19

Inform Med Unlocked. 2021:22:100504. doi: 10.1016/j.imu.2020.100504. Epub 2020 Dec 23.

Authors

Affiliations

¹ Sinhgad Technical Education Society's, Smt. Kashibai Navale College of Pharmacy, Pune, Maharashtra, India.
² School of Pharmacy, University of East Anglia, Norwich Research Park, Norwich, UK.
³ Department of Pharmacology and Toxicology, KLE College of Pharmacy Belagavi, KLE Academy of Higher Education and Research (KAHER), Belagavi, 590010, India.
⁴ PES's Rajaram and Tarabai Bandekar College of Pharmacy, Ponda, Goa University, Goa, 403401, India.
⁵ Department of Botany, A. Veeriya Vandayar Memorial Sri Pushpam College (Autonomous), Affiliated to Bharathidasan University, Poondi, Thanjavur, 613 503, India.
⁶ Department of Pharmaceutical Sciences, Mohanlal Shukhadia University, Udaipur, Rajasthan, 313 001, India.
⁷ Department of Pharmaceutical Sciences, R.T.M. University, Nagpur, Maharashtra, 440033, India.
⁸ School of Pharmaceutical Technology, Adamas University, Kolkata, 700126, West Bengal, India.
⁹ Regional Ayurveda Research Institute for Drug Development, Gwalior, 474009, Madhya Pradesh, India.
¹⁰ Department of Pharmacognosy and Phytochemistry, Goa College of Pharmacy, Panaji, Goa University, Goa, 403 001, India.

Abstract

Bioflavonoids are the largest group of plant-derived polyphenolic compounds with diverse biological potential and have also been proven efficacious in the treatment of Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS). The present investigation validates molecular docking, simulation, and MM-PBSA studies of fifteen bioactive bioflavonoids derived from plants as a plausible potential antiviral in the treatment of COVID-19. Molecular docking studies for 15 flavonoids on the three SARS CoV-2 proteins, non-structural protein-15 Endoribonuclease (NSP15), the receptor-binding domain of spike protein (RBD of S protein), and main protease (M^pro/3CL^pro) were performed and selected protein-ligand complexes were subjected to Molecular Dynamics simulations. The molecular dynamics trajectories were subjected to free energy calculation by the MM-PBSA method. All flavonoids were further assessed for their effectiveness as adjuvant therapy by network pharmacology analysis on the target proteins. The network pharmacology analysis suggests the involvement of selected bioflavonoids in the modulation of multiple signaling pathways like p53, FoxO, MAPK, Wnt, Rap1, TNF, adipocytokine, and leukocyte transendothelial migration which plays a significant role in immunomodulation, minimizing the oxidative stress and inflammation. Molecular docking and molecular dynamics simulation studies illustrated the potential of glycyrrhizic acid, amentoflavone, and mulberroside in inhibiting key SARS-CoV-2 proteins and these results could be exploited further in designing future ligands from natural sources.

Keywords: 2019-nCoV, 2019 Novel Coronavirus; Amentoflavone; Bioflavonoids; COVID-19, Coronavirus Disease-2019; CoV, Corona Virus; Glycyrrhizic acid; In-silico study; MD, Molecular Dynamics; MM-PBSA, Molecular Mechanics Poisson-Boltzmann Surface Area; Mulberroside; NSP, Non-structural Protein; Novel Coronavirus-2; OPLS, Optimized Potentials for Liquid Simulations; ORF, Open Reading Frame; RBD, Receptor Binding Domain; RMSD, Root Mean Square Deviation; SARS, Severe Acute Respiratory syndrome; SARS-CoV-2, Severe Acute Respiratory syndrome Coronavirus-2; SDF, Structure Data File; WHO, World Health Organization; Å, Angstrom.