Structure-based virtual screening suggests inhibitors of 3-Chymotrypsin-Like Protease of SARS-CoV-2 from Vernonia amygdalina and Occinum gratissimum

https://doi.org/10.1016/j.compbiomed.2021.104671Get rights and content

Highlights

  • Antiviral food herbs and spices are potential bioresources for preventive nutraceuticals and/or antiviral drugs in COVID-19.

  • Structure-based virtual screening revealed phytocompounds derived from two dietary plants as potential inhibitors of SARS-CoV-2 3-Chymotrypsin-Like Protease.

  • Two drug-like terpenoid structures (neoandrographolide and vernolide) were identified as hit compounds.

  • The phytocompounds may inhibit SARS-CoV-2 3CLpro by interfering with the tetrahedral oxyanion intermediate formation during the proteolytic activity of the enzyme.

  • Molecular dynamics simulation and binding free energy calculation revealed that the terpenoid-enzyme complexes exhibit strong interactions and structural stability.

Abstract

Antiviral culinary plants are potential bioresources for preventive nutraceuticals and/or antiviral drugs in COVID-19. Structure-based virtual screening was undertaken to screen 173 compounds previously reported from Vernonia amygdalina and Occinum gratissimum for direct interaction with the active site of the 3-Chymotrypsin-Like Protease (3CLpro) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Based on docking scores and comparison with reference inhibitors, a hit-list of 10 top phytocompounds was defined, which also had strong interactions with the catalytic centre of 3CLpro from three related strains of coronavirus (SARS-CoV, MERS-CoV, HKU4). Among these, six compounds (neoandrographolide, vernolide, isorhamnetin, chicoric acid, luteolin, and myricetin) exhibited the highest binding tendencies to the equilibrated conformers of SARS-CoV-2 3CLpro in an in-depth docking analysis to 5 different representative conformations from the cluster analysis of the molecular dynamics simulation (MDS) trajectories of the protein. In silico drug-likeness analyses revealed two drug-like terpenoids viz: neoandrographolide and vernolide as promising inhibitors of SARS-CoV-2 3CLpro. These structures were accommodated within the substrate-binding pocket; and interacted with the catalytic dyad (Cys145 and His41), the oxyanion loop (residues 138–145), and the S1/S2 sub-sites of the enzyme active site through the formation of an array of hydrogen bonds and hydrophobic interactions. Molecular dynamics simulation and binding free energy calculation revealed that the terpenoid-enzyme complexes exhibit strong interactions and structural stability. Therefore, these compounds may stabilize the conformation of the flexible oxyanion loop; and thereby interfere with the tetrahedral oxyanion intermediate formation during the proteolytic activity of the enzyme.

Keywords

Food herbs
Coronavirus
COVID-19
Phytochemicals
Terpenoids
Molecular docking
Molecular dynamics simulations

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Dr. Gideon A. Gyebi is currently a lecturer at the Department of Biochemistry, Faculty of Science and Technology Bingham University, Karu, Nasarawa, Nigeria. He obtained his Ph.D in Biochemistry in cancer chemoprevention and toxicology from the Department of Biochemistry, University of Ilorin, Kwara state, Nigeria. He was a former faculty member of the College of Natural and Applied Sciences, Salem University, Nigeria. He was a visiting researcher to the Department of Chemistry and Biomolecular Sciences, Faculty of Engineering, and the Anaerobic Research Unit of Gifu University, (1-1 Yanagido Gifu) Japan. His research interests are natural product Chemistry, Bioinformatics malaria and cancer chemotherapy. He is a pioneer member of the PhytoBioNet: Phytochemistry and Bioinformatic Network.

Dr. Abdo A. Elfiky I'm working in the Biophysics Department, Faculty of Sciences, Cairo University, Giza, Egypt as a Lecturer starting from the year 2013 then Associate Professor 2019. My interest in Molecular Biophysics pushes me to work in Structural Bioinformatics and Drug Design to find potent inhibitors against viral and pathogenic fungal proteins utilizing in silico techniques. During the past 6 years, I focused my research on polymerase protein due to its vital role in the life cycle of the pathogenic organisms. I studied also other proteins like protease, estrogen receptors and kinases. Currently, I'm working on fungal CotH kinase family proteins crucial for Mucormycosis virulence and the unfolded protein response master chaperone protein, GRP78.

Oludare M. Ogunyemi is an advanced PhD candidate in the Department of Biochemistry, College of Medicine, University of Ibadan and currently a lecturer in the Department of Biochemistry, Salem University, Nigeria. He is a recipient of several awards which include the African-German Network of Excellence in Science Mobility grant, 2016. He was a visiting pre-doctoral researcher to the Food Security and Safety Research Niche, North-West University, Mafikeng, South Africa. He is a reviewer of manuscripts for reputable journals. He is a pioneer member of the Phytochemistry and Bioinformatic Network (PhytoBioNet). His hopes to conduct research in the area of Human nutraceuticals and bioinformatics.

Ibrahim Mohamed Ibrahim is a master degree candidate in Department of Biophysics, Cairo University, Egypt. He is a researcher in Dr. Abdo A. Elfiky research group. He has published several papers related to structural bioinformatics.

Dr. Adegbenro P. Adegunloye is a Clinical Biochemist with keen interest in malaria chemotherapy and biochemical toxicology. He obtained his Ph.D. in Biochemistry from University of Ilorin, Nigeria. He was a former lecturer at Wesley University of Science and Technology, Ondo, Nigeria.

Professor Joseph O. Adebayo is currently a professor of clinical biochemistry and biochemical toxicology at the Department of Biochemistry, Faculty of Life Sciences, University of Ilorin, Nigeria. He obtained his Ph.D in Biochemistry (Clinical option) from the University of Ilorin, Kwara state, Nigeria. He is a former postdoctoral fellow at the Instituto Ren'e Rachou, FIOCRUZ, Belo Horizonte MG, Brasil. His research interests are malaria chemotherapy and diagnosis. He has presented various academic as well as research-based papers at several national and international conferences including Society of Toxicology USA. He has supervised several Ph.D students, one of such is Dr. Gideon A. Gyebi.

Professor C.O.O Olaiya is a professor and the Director of Nutritional and Industrial Biochemistry Research Unit, Department of Biochemistry, College of Medicine, University of Ibadan, Nigeria. He obtained his Ph.D. in Biochemistry from the University of Ibadan, Nigeria. He is a recipient of several awards such as the TWAS Postdoctoral Research Fellowship Award, 2009 among others. He was a former postdoctoral fellow at the International Center for Chemical and Biological Sciences, University of Karachi, Karachi, Pakistan and Visiting Professor at Kampala International University, Uganda. His current research interests include: Plant metabolites and biofortification of food crops, modulation of plant responses to abiotic stress, fermentation technology, and nutraceuticals. He has presented various academic as well as research-based papers at many national and international conferences. He has trained and supervised quite a number of Ph.D students to date.

Joshua O. Ocheje received his M.Sc. Analytical Chemistry from the University of Ibadan and currently works as a Lecturer in the Department of Pure and Industrial Chemistry, Nnamdi Azikiwe University, Nigeria. He is a recipient of the National Youth Service Corps (NYSC) Presidential Honors Award 2019. His research interests include the use of biochemistry and X-ray crystallography to study the structure and function of enzymes and other important proteins as drug targets.

Modupe Mercy Fabusiwa recently completed her B.Sc. degree in Biochemistry from Salem University, Nigeria. She has published papers related to food and nutritional biochemistry.

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