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INFECTIOUS DISEASES / BASIC RESEARCH
Identification of natural compounds (proanthocyanidin and rhapontin) as high-affinity inhibitors of SARS-CoV-2 Mpro and PLpro using computational strategies
1
Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
2
Aligarh College of Education, Aligarh, India
3
Department of Orthopaedic Surgery, New York University, School of Medicine, New York, USA
4
Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia
Submission date: 2020-10-16
Final revision date: 2021-02-09
Acceptance date: 2021-02-26
Online publication date: 2021-03-20
Corresponding author
Md Tabish Rehman
Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh-11451, Saudi Arabia, 11451, Riyadh, Saudi Arabia
Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh-11451, Saudi Arabia, 11451, Riyadh, Saudi Arabia
Arch Med Sci 2024;20(2):567-581
KEYWORDS
TOPICS
ABSTRACT
Introduction:
The emergence of a new and highly pathogenic coronavirus (SARS-CoV-2) in Wuhan (China) and its spread worldwide has resulted in enormous social and economic losses. Amongst many proteins encoded by the SARS-CoV-2 genome, the main protease (Mpro) or chymotrypsin-like cysteine protease (3CLpro) and papain-like protease (PLpro) serve as attractive drug targets.
Material and methods:
We screened a library of 2267 natural compounds against Mpro and PLpro using high throughput virtual screening (HTVS). Fifty top-scoring compounds against each protein in HTVS were further evaluated by standard-precision (SP) docking. Compounds with SP docking energy of ≤ –8.0 kcal/mol against Mpro and ≤ –5.0 kcal/mol against PLpro were subjected to extra-precision (XP) docking. Finally, six compounds against each target proteins were identified and subjected to Prime/MM-GBSA free energy calculations. Compounds with the lowest Prime/MM-GBSA energy were subjected to molecular dynamics simulation to evaluate the stability of protein-ligand complexes.
Results:
Proanthocyanidin and rhapontin were identified as the most potent inhibitors of Mpro and PLpro, respectively. Analysis of protein-inhibitor interaction revealed that both protein-inhibitor complexes were stabilized by hydrogen bonding and hydrophobic interactions. Proanthocyanidin interacted with the catalytic residues (His41 and Cys145) of Mpro, while rhapontin contacted the active site residues (Trp106, His272, Asp286) of PLpro. The docking energies of proanthocyanidin and rhapontin towards their respective targets were –10.566 and –10.022 kcal/mol.
Conclusions:
This study’s outcome may support application of proanthocyanidin and rhapontin as a scaffold to build more potent inhibitors with desirable drug-like properties. However, it requires further validation by in vitro and in vivo studies.
The emergence of a new and highly pathogenic coronavirus (SARS-CoV-2) in Wuhan (China) and its spread worldwide has resulted in enormous social and economic losses. Amongst many proteins encoded by the SARS-CoV-2 genome, the main protease (Mpro) or chymotrypsin-like cysteine protease (3CLpro) and papain-like protease (PLpro) serve as attractive drug targets.
Material and methods:
We screened a library of 2267 natural compounds against Mpro and PLpro using high throughput virtual screening (HTVS). Fifty top-scoring compounds against each protein in HTVS were further evaluated by standard-precision (SP) docking. Compounds with SP docking energy of ≤ –8.0 kcal/mol against Mpro and ≤ –5.0 kcal/mol against PLpro were subjected to extra-precision (XP) docking. Finally, six compounds against each target proteins were identified and subjected to Prime/MM-GBSA free energy calculations. Compounds with the lowest Prime/MM-GBSA energy were subjected to molecular dynamics simulation to evaluate the stability of protein-ligand complexes.
Results:
Proanthocyanidin and rhapontin were identified as the most potent inhibitors of Mpro and PLpro, respectively. Analysis of protein-inhibitor interaction revealed that both protein-inhibitor complexes were stabilized by hydrogen bonding and hydrophobic interactions. Proanthocyanidin interacted with the catalytic residues (His41 and Cys145) of Mpro, while rhapontin contacted the active site residues (Trp106, His272, Asp286) of PLpro. The docking energies of proanthocyanidin and rhapontin towards their respective targets were –10.566 and –10.022 kcal/mol.
Conclusions:
This study’s outcome may support application of proanthocyanidin and rhapontin as a scaffold to build more potent inhibitors with desirable drug-like properties. However, it requires further validation by in vitro and in vivo studies.
REFERENCES (55)
1.
Schoeman D, Fielding BC. Coronavirus envelope protein: current knowledge. Virol J 2019; 16: 69.
2.
She J, Jiang J, Ye L, Hu L, Bai C, Song Y. 2019 novel coronavirus of pneumonia in Wuhan, China: emerging attack and management strategies. Clin Transl Med 2020; 9: 19.
3.
Woo PCY, Huang Y, Lau SKP, Yuen KY. Coronavirus genomics and bioinformatics analysis. Viruses 2010; 2: 1804-20.
4.
Song Z, Xu Y, Bao L, et al. From SARS to MERS, thrusting coronaviruses into the spotlight. Viruses 2019; 11: 59.
5.
Romano M, Ruggiero A, Squeglia F, Maga G, Berisio R. A structural view of SARS-CoV-2 RNA replication machinery: RNA synthesis, proofreading and final capping. Cells 2020; 9: 1267.
6.
Xue X, Yu H, Yang H, et al. Structures of two coronavirus main proteases: implications for substrate binding and antiviral drug design. J Virol 2008; 82: 2515-27.
7.
Báez-Santos YM, St. John SE, Mesecar AD. The SARS-coronavirus papain-like protease: structure, function and inhibition by designed antiviral compounds. Antivir Res 2015; 115: 21-38.
8.
Xu J, Li X, Jiang B, et al. Antiviral immunotoxin against bovine herpesvirus-1: targeted inhibition of viral replication and apoptosis of infected cell. Front Microbiol 2018; 9: 653.
9.
Zhou Y, Hou Y, Shen J, Huang Y, Martin W, Cheng F. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov 2020; 6: 14.
10.
Ojha PK, Krishna JG, Roy K, Leszczynski J. Therapeutics for COVID-19: from computation to practices-where we are, where we are heading to. Mol Divers 2020; 25: 625-59.
11.
Reiner Z, Hatamipour M, Banach M, et al. Statins and the COVID-19 main protease: in silico evidence on direct interaction. Arch Med Sci 2020; 16: 490-6.
12.
Borgio JF, Alsuwat HS, Al Otaibi WM, et al. State-of-the-art tools unveil potent drug targets amongst clinically approved drugs to inhibit helicase in SARS-CoV-2. Arch Med Sci 2020; 16: 508-18.
13.
Azeez SA, Ghalib Alhashim Z, Al Otaibi WM, et al. State-of-the-art tools to identify druggable protein ligand of SARS-CoV-2. Arch Med Sci 2020; 16: 497-507.
14.
Jo S, Kim S, Shin DH, Kim MS. Inhibition of SARS-CoV 3CL protease by flavonoids. J Enzyme Inhib Med Chem 2020; 35: 145-51.
15.
Jo S, Kim H, Kim S, Shin DH, Kim MS. Characteristics of flavonoids as potent MERS-CoV 3C-like protease inhibitors. Chem Biol Drug Des 2019; 94: 2023-30.
16.
AlAjmi MF, Azhar A, Owais M, et al. Antiviral potential of some novel structural analogs of standard drugs repurposed for the treatment of COVID-19. J Biomol Struct Dyn 2021; 39: 6676-88.
17.
Parvez MK, Rehman MT, Alam P, Al-Dosari MS, Alqasoumi SI, Alajmi MF. Plant-derived antiviral drugs as novel hepatitis B virus inhibitors: cell culture and molecular docking study. Saudi Pharm J 2019; 27: 389-400.
18.
AlAjmi MF, Rehman MT, Hussain A, Rather GM. Pharmacoinformatics approach for the identification of Polo-like kinase-1 inhibitors from natural sources as anticancer agents. Int J Biol Macromol 2018; 116: 173-81.
19.
Rehman M, AlAjmi M, Hussain A, Rather G, Khan M. High-throughput virtual screening, molecular dynamics simulation, and enzyme kinetics identified ZINC84525623 as a potential inhibitor of NDM-1. Int J Mol Sci 2019; 20: 819.
20.
Rehman MT, Shamsi H, Khan AU. Insight into the binding mechanism of imipenem to human serum albumin by spectroscopic and computational approaches. Mol Pharm 2014; 11: 1785-97.
21.
Rehman MT, Ahmed S, Khan AU. Interaction of meropenem with ‘N’ and ‘B’ isoforms of human serum albumin: a spectroscopic and molecular docking study. J Biomol Struct Dyn 2016; 34: 1849-64.
22.
Verma P, Tiwari M, Tiwari V. In silico high-throughput virtual screening and molecular dynamics simulation study to identify inhibitor for AdeABC efflux pump of Acinetobacter baumannii. J Biomol Struct Dyn 2018; 36: 1182-94.
23.
Florkowski CM. Sensitivity, specificity, receiver-operating characteristic (ROC) curves and likelihood ratios: communicating the performance of diagnostic tests. Clin Biochem Rev 2008; 29 Suppl 1: S83-7.
24.
Rehman MT, AlAjmi MF, Hussain A. Natural compounds as inhibitors of SARS-CoV-2 main protease (3CLpro): a molecular docking and simulation approach to combat COVID-19. Curr Pharm Des 2021; 27: 3577-89.
25.
Al-Shabib NA, Khan JM, Malik A, et al. Molecular interactions of food additive dye quinoline yellow (Qy) with alpha-lactalbumin: spectroscopic and computational studies. J Mol Liq 2020; 311: 113215.
26.
Martyna GJ, Tobias DJ, Klein ML. Constant pressure molecular dynamics algorithms. J Chem Phy 1994; 101: 4177-89.
27.
Brańka AC. Nosé-Hoover chain method for nonequilibrium molecular dynamics simulation. Phys Rev E 2000; 61: 4769-73.
28.
Mohammad T, Shamsi A, Anwar S, et al. Identification of high-affinity inhibitors of SARS-CoV-2 main protease: towards the development of effective COVID-19 therapy. Virus Res 2020; 288: 198102.
29.
Guo YR, Cao QD, Hong ZS, et al. The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreak – an update on the status. Mil Med Res 2020; 7: 11.
30.
Cinatl J, Morgenstern B, Bauer G, Chandra P, Rabenau H, Doerr HW. Glycyrrhizin, an active component of liquorice roots, and replication of SARS-associated coronavirus. Lancet 2003; 361: 2045-6.
31.
Wang Z, Chen X, Lu Y, Chen F, Zhang W. Clinical characteristics and therapeutic procedure for four cases with 2019 novel coronavirus pneumonia receiving combined Chinese and Western medicine treatment. Biosci Trends 2020; 14: 64-8.
32.
Kuntz ID, Blaney JM, Oatley SJ, Langridge R, Ferrin TE. A geometric approach to macromolecule-ligand interactions. J Mol Biol 1982; 161: 269-88.
33.
Zhang L, Lin D, Sun X, et al. Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved a-ketoamide inhibitors. Science 2020; 368: 409-12.
34.
Morse JS, Lalonde T, Xu S, Liu WR. Learning from the past: possible urgent prevention and treatment options for severe acute respiratory infections caused by 2019-nCoV. ChemBioChem 2020; 21: 730-8.
35.
Jin Z, Du X, Xu Y, et al. Structure of Mpro from COVID-19 virus and discovery of its inhibitors. Nature 2020; 582: 289-93.
36.
Palese LL. The structural landscape of SARS-CoV-2 main protease: hints for inhibitor search. ChemRxiv 2020. https://doi.org/10.26434/chemr....
37.
Kumar V, Rou K. Development of a simple, interpretable and easily transferable QSAR model for quick screening antiviral databases in search of novel 3Clike protease (3CLpro) enzyme inhibitors against SARS-CoV diseases. SAR QSAR Environ Res 2020; 31: 511-26.
38.
de la Iglesia R, Milagro FI, Campión J, Boqué N, Martínez JA. Healthy properties of proanthocyanidins. BioFactors 2010; 36: 159-68.
39.
Marie A. Oligomeric proanthocyanidin complexes: history, structure, and phytopharmaceutical applications. Altern Med Rev 2000; 5: 144-51.
40.
Shahat AA, Cos P, De Bruyne T, et al. Antiviral and antioxidant activity of flavonoids and proanthocyanidins from Crataegus sinaica. Planta Med 2002; 68: 539-41.
41.
Zhang M, Wu Q, Chen Y, et al. Inhibition of proanthocyanidin A2 on porcine reproductive and respiratory syndrome virus replication in vitro. PLoS One 2018; 13: e0193309.
42.
Gallina L, Dal Pozzo F, Galligioni V, Bombardelli E, Scagliarini A. Inhibition of viral RNA synthesis in canine distemper virus infection by proanthocyanidin A2. Antivir Res 2011; 92: 447-52.
43.
Zhuang M, Jiang H, Suzuki Y, et al. Procyanidins and butanol extract of Cinnamomi Cortex inhibit SARS-CoV infection. Antivir Res 2009; 82: 73-81.
44.
Ratia K, Saikatendu KS, Santarsiero BD, et al. Severe acute respiratory syndrome coronavirus papain-like protease: structure of a viral deubiquitinating enzyme. PNAS 2006; 103: 5717-22.
45.
Ratia K, Kilianski A, Baez-Santos YM, Baker SC, Mesecar A. Structural basis for the ubiquitin-linkage specificity and deISGylating activity of SARS-CoV papain-like protease. PLoS Pathog 2014; 10: e1004113.
46.
Calistri A, Munegato D, Carli I, Parolin C, Palù G. The ubiquitin-conjugating system: multiple roles in viral replication and infection. Cells 2014; 3: 386-417.
47.
Barretto N, Jukneliene D, Ratia K, Chen Z, Mesecar AD, Baker SC. The papain-like protease of severe acute respiratory syndrome coronavirus has deubiquitinating activity. J Virol 2005; 79: 15189-98.
48.
Lindner HA, Fotouhi-Ardakani N, Lytvyn V, Lachance P, Sulea T, Ménard R. The papain-like protease from the severe acute respiratory syndrome coronavirus is a deubiquitinating enzyme. J Virol 2005; 79: 15199-208.
49.
Amin SA, Ghosh K, Gayen S, Jha T. Chemical-informatics approach to COVID-19 drug discovery: Monte Carlo based QSAR, virtual screening and molecular docking study of some in-house molecules as papainlike protease (PLpro) inhibitors, J Biomol Struct Dyn 2021; 39: 4764-73.
50.
Kolodziejczyk-Czepas J, Czepas J. Rhaponticin as an anti-inflammatory component of rhubarb: a minireview of the current state of the art and prospects for future research. Phytochem Rev 2019; 18: 1375-86.
51.
Gelpi J, Hospital A, Goñi R, Orozco M. Molecular dynamics simulations: advances and applications. Adv Appl Bioinform Chem 2015; 8: 37-47.
52.
Mohammad T, Arif K, Alajmi MF, et al. Identification of high-affinity inhibitors of pyruvate dehydrogenase kinase-3: towards therapeutic management of cancer. J Biomol Struct Dyn 2020; 1-9. doi:10.1080/07391102.2020.1711810.
53.
Shamsi A, Mohammad T, Anwar S, et al. Glecaprevir and Maraviroc are high-affinity inhibitors of SARS-CoV-2 main protease: possible implication in COVID-19 therapy. Biosci Rep 2020; 40: BSR20201256.
54.
Rodier F, Bahadur RP, Chakrabarti P, Janin J. Hydration of protein-protein interfaces. Proteins 2005; 60: 36-45.
55.
Guan L, Yang H, Cai Y, et al. ADMET-score-a comprehensive scoring function for evaluation of chemical drug-likeness. Med Chem Comm 2019; 10: 148-57.
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