Molecular docking and dynamics studies show: Phytochemicals from Papaya leaves extracts as potential inhibitors of SARS–CoV–2 proteins targets and TNF–alpha and alpha thrombin human targets for combating COVID-19

Mohd Shukri Abd Shukor; Mohd Yunus Abd Shukor; Mohd Shukri Abd Shukor; Mohd Yunus Abd Shukor

doi:10.3934/molsci.2023015

AIMS Molecular Science

2023, Volume 10, Issue 3: 213-262. doi: 10.3934/molsci.2023015

Previous Article Next Article

Research article

Molecular docking and dynamics studies show: Phytochemicals from Papaya leaves extracts as potential inhibitors of SARS–CoV–2 proteins targets and TNF–alpha and alpha thrombin human targets for combating COVID-19

Mohd Shukri Abd Shukor ¹,
Mohd Yunus Abd Shukor ^{2
,
,}

1.
Snoc International Sdn Bhd, Lot 343, Jalan 7/16 Kawasan Perindustrian Nilai 7, Inland Port, 71800, Negeri Sembilan, Malaysia
2.
Department of Biochemistry, Faculty of Biotechnology and Biomolecular Sciences, University Putra Malaysia, UPM 43400 Serdang, Selangor, Malaysia

Received: 25 May 2023 Revised: 27 July 2023 Accepted: 10 September 2023 Published: 25 September 2023

Tackling COVID-19 requires halting virus proliferation and reducing viral complications in humans. Papaya leaf extract (PLE) is well known for its ability to inhibit numerous viral replications in vitro and in vivo and reduce viral complications in humans such as thrombocytopenia and cytokine storm. The goal of this research is to evaluate the possible use of papaya leaf extract as a multifaceted antiviral and potential therapy for COVID-19 using an in-silico docking followed by a 100 ns molecular dynamics simulation (MDS) approach. The targeted proteins are the SARS-CoV-2's proteins such as the nucleocapsid, main protease (MPro), RNA-dependent RNA polymerase (RdRP), spike protein (Wuhan, Delta, and Omicron variants) and human TNF-alpha and alpha-thrombin protein targets. Several compounds from PLE such as protodioscin, clitorin, glycyrrhizic acid, manghaslin, kaempferol–3–(2g–glucosylrutinoside), rutin, isoquercetrin and acacic acid were found to exhibit strong binding to these targets. The free energies of binding (Autodock) with protodioscin, the best PLE compound for nucleocapsid, main protease (MPro), RdRP and spike protein were –13.83, –13.19, –11.62 and –10.77 (Omicron), kcal/mol, respectively, while the TNF-alpha and alpha-thrombin binding free energies were –13.64 and –13.50 kcal/mol, respectively. The calculated inhibition constants for protodioscin were in the nanomolar and picomolar range at 216.34, 27.07, 73.28, and 99.93 pM, respectively, whilst RdRp and spike protein (Omicron) were in the nanomolar range at 3.02 and 12.84 nM, respectively. Protodioscin interacted with key residues of all protein targets. The binding affinity poses were confirmed by molecular dynamics simulation. Analysis of the binding affinities calculated employing the molecular mechanics-Poisson–Boltzmann surface area (MM-PBSA) shows favorable interaction between protodioscin, and all targets based on total binding-free energies corroborating the Autodock's docking results. In conclusion, compounds from PLE, especially protodioscin have good potentials in combating COVID-19.
- COVID-19,
- SARS-CoV-2,
- papaya leaves extract,
- in silico,
- long COVID
Citation: Mohd Shukri Abd Shukor, Mohd Yunus Abd Shukor. Molecular docking and dynamics studies show: Phytochemicals from Papaya leaves extracts as potential inhibitors of SARS–CoV–2 proteins targets and TNF–alpha and alpha thrombin human targets for combating COVID-19[J]. AIMS Molecular Science, 2023, 10(3): 213-262. doi: 10.3934/molsci.2023015

Related Papers:

Abstract

Tackling COVID-19 requires halting virus proliferation and reducing viral complications in humans. Papaya leaf extract (PLE) is well known for its ability to inhibit numerous viral replications in vitro and in vivo and reduce viral complications in humans such as thrombocytopenia and cytokine storm. The goal of this research is to evaluate the possible use of papaya leaf extract as a multifaceted antiviral and potential therapy for COVID-19 using an in-silico docking followed by a 100 ns molecular dynamics simulation (MDS) approach. The targeted proteins are the SARS-CoV-2's proteins such as the nucleocapsid, main protease (MPro), RNA-dependent RNA polymerase (RdRP), spike protein (Wuhan, Delta, and Omicron variants) and human TNF-alpha and alpha-thrombin protein targets. Several compounds from PLE such as protodioscin, clitorin, glycyrrhizic acid, manghaslin, kaempferol–3–(2g–glucosylrutinoside), rutin, isoquercetrin and acacic acid were found to exhibit strong binding to these targets. The free energies of binding (Autodock) with protodioscin, the best PLE compound for nucleocapsid, main protease (MPro), RdRP and spike protein were –13.83, –13.19, –11.62 and –10.77 (Omicron), kcal/mol, respectively, while the TNF-alpha and alpha-thrombin binding free energies were –13.64 and –13.50 kcal/mol, respectively. The calculated inhibition constants for protodioscin were in the nanomolar and picomolar range at 216.34, 27.07, 73.28, and 99.93 pM, respectively, whilst RdRp and spike protein (Omicron) were in the nanomolar range at 3.02 and 12.84 nM, respectively. Protodioscin interacted with key residues of all protein targets. The binding affinity poses were confirmed by molecular dynamics simulation. Analysis of the binding affinities calculated employing the molecular mechanics-Poisson–Boltzmann surface area (MM-PBSA) shows favorable interaction between protodioscin, and all targets based on total binding-free energies corroborating the Autodock's docking results. In conclusion, compounds from PLE, especially protodioscin have good potentials in combating COVID-19.

Acknowledgments

We are indebted to the ResearchGate community for helpful troubleshooting ideas during the completion of this work. We thank Ismail Shukor for setting up the GPU system and the Linux configuration and Nazirah Shukor for financing the project.

Conflicts of interest

The authors declare no conflict of interest.

References

[1]	Iguchi T, Umeda H, Kojima M, et al. (2021) Cumulative adverse event reporting of anaphylaxis after mRNA COVID-19 vaccine (Pfizer-BioNTech) injections in Japan: The first-month report. Drug Saf 44: 1209-1214. https://doi.org/10.1007/s40264-021-01104-9
[2]	Costantino M, Sellitto C, Conti V, et al. (2022) Adverse events associated with BNT162b2 and AZD1222 vaccines in the real world: Surveillance report in a single Italian vaccine center. J Clin Med 11: 1408. https://doi.org/10.3390/jcm11051408
[3]	Halstead SB (2018) Safety issues from a Phase 3 clinical trial of a live-attenuated chimeric yellow fever tetravalent dengue vaccine. Hum Vaccin Immunother 14: 2158-2162. https://doi.org/10.1080/21645515.2018.1445448
[4]	Clothier HJ, Lawrie J, Russell MA, et al. (2019) Early signal detection of adverse events following influenza vaccination using proportional reporting ratio, Victoria, Australia. PLoS One 14: e0224702. https://doi.org/10.1371/journal.pone.0224702
[5]	Masuka JT, Khoza S (2019) Adverse events following immunisation (AEFI) reports from the Zimbabwe expanded programme on immunisation (ZEPI): An analysis of spontaneous reports in Vigibase^® from 1997 to 2017. BMC Public Health 19: 1166. https://doi.org/10.1186/s12889-019-7482-x
[6]	Reyes MSGL, Dee EC, Ho BL (2021) Vaccination in the Philippines: experiences from history and lessons for the future. Hum Vaccin Immunother 17: 1873-1876. https://doi.org/10.1080/21645515.2020.1841541
[7]	Avolio E, Carrabba M, Kavanagh Williamson M, et al. (2021) The SARS-CoV-2 Spike protein alters human cardiac pericyte function and interaction with endothelial cells through a non-infective mechanism involving activation of CD₁₄₇ receptor signalling. Eur Heart J 42: ehab724.3383. https://doi.org/10.1093/eurheartj/ehab724.3383
[8]	Avolio E, Carrabba M, Milligan R, et al. (2021) The SARS-CoV-2 Spike protein disrupts human cardiac pericytes function through CD₁₄₇ receptor-mediated signalling: a potential non-infective mechanism of COVID-19 microvascular disease. Clin Sci (Lond) 135: 2667-2689. https://doi.org/10.1042/CS20210735
[9]	Khaddaj-Mallat R, Aldib N, Bernard M, et al. (2021) SARS-CoV-2 deregulates the vascular and immune functions of brain pericytes via Spike protein. Neurobiol Dis 161: 105561. https://doi.org/10.1016/j.nbd.2021.105561
[10]	Rhea EM, Logsdon AF, Hansen KM, et al. (2021) The S1 protein of SARS-CoV-2 crosses the blood–brain barrier in mice. Nat Neurosci 24: 368-378. https://doi.org/10.1038/s41593-020-00771-8
[11]	Singh RD, Barry MA, Croatt AJ, et al. (2022) The spike protein of SARS-CoV-2 induces heme oxygenase-1: Pathophysiologic implications. Biochim Biophys Acta Mol Basis Dis 1868: 166322. https://doi.org/10.1016/j.bbadis.2021.166322
[12]	Ventura Fernandes BH, Feitosa NM, Barbosa AP, et al. (2022) Toxicity of spike fragments SARS-CoV-2 S protein for zebrafish: A tool to study its hazardous for human health?. Sci Total Environ 813: 152345. https://doi.org/10.1016/j.scitotenv.2021.152345
[13]	Greinacher A, Selleng K, Palankar R, et al. (2021) Insights in ChAdOx1 nCoV-19 vaccine-induced immune thrombotic thrombocytopenia. Blood 138: 2256-2268. https://doi.org/10.1182/blood.2021013231
[14]	Greinacher A, Langer F, Makris M, et al. (2022) Vaccine-induced immune thrombotic thrombocytopenia (VITT): Update on diagnosis and management considering different resources. J Thromb Haemost 20: 149-156. https://doi.org/10.1111/jth.15572
[15]	Lavin M, Elder PT, O'Keeffe D, et al. (2021) Vaccine-induced immune thrombotic thrombocytopenia (VITT)–a novel clinico-pathological entity with heterogeneous clinical presentations. Br J Haematol 195: 76-84. https://doi.org/10.1111/bjh.17613
[16]	Leung HHL, Perdomo J, Ahmadi Z, et al. (2022) NETosis and thrombosis in vaccine-induced immune thrombotic thrombocytopenia. Nat Commun 13: 5206. https://doi.org/10.1038/s41467-022-32946-1
[17]	Iba T, Levy JH (2022) Thrombosis and thrombocytopenia in COVID-19 and after COVID-19 vaccination. Trends Cardiovasc Med 32: 249-256. https://doi.org/10.1016/j.tcm.2022.02.008
[18]	Franchini M, Liumbruno GM, Pezzo M (2021) COVID-19 vaccine-associated immune thrombosis and thrombocytopenia (VITT): Diagnostic and therapeutic recommendations for a new syndrome. Eur J Haematol 107: 173-180. https://doi.org/10.1111/ejh.13665
[19]	Jermain B, Hanafin PO, Cao Y, et al. (2020) Development of a minimal physiologically-based pharmacokinetic model to simulate lung exposure in humans following oral administration of ivermectin for COVID-19 drug repurposing. J Pharm Sci 109: 3574-3578. https://doi.org/10.1016/j.xphs.2020.08.024
[20]	Singh TU, Parida S, Lingaraju MC, et al. (2020) Drug repurposing approach to fight COVID-19. Pharmacol Rep 72: 1479-1508. https://doi.org/10.1007/s43440-020-00155-6
[21]	Dittmar M, Lee JS, Whig K, et al. (2021) Drug repurposing screens reveal cell-type-specific entry pathways and FDA-approved drugs active against SARS-Cov-2. Cell Rep 35: 108959. https://doi.org/10.1016/j.celrep.2021.108959
[22]	Hiltzik M (2021) Column: Major study of Ivermectin, the anti-vaccine crowd's latest COVID drug, finds ‘no effect whatsoever’.Los Angeles Times. Available from: https://www.latimes.com/business/story/2021-08-11/ivermectin-no-effect-covid
[23]	Yadav R, Hasan S, Mahato S, et al. (2021) Molecular docking, DFT analysis, and dynamics simulation of natural bioactive compounds targeting ACE2 and TMPRSS2 dual binding sites of spike protein of SARS CoV-2. J Mol Liq 342: 116942. https://doi.org/10.1016/j.molliq.2021.116942
[24]	Moharana M, Das A, Sahu SN, et al. (2022) Evaluation of binding performance of bioactive compounds against main protease and mutant model spike receptor binding domain of SARS-CoV-2: Docking, ADMET properties and molecular dynamics simulation study. J Indian Chem Soc 99: 100417. https://doi.org/10.1016/j.jics.2022.100417
[25]	Rastmanesh R, Marotta F, Tekin I (2020) Call for mobilization of functional foods, antioxidants, and herbal antivirals in support of international campaign to control coronavirus. Bioact Comp Health Dis 3: 90-94. https://doi.org/10.31989/bchd.v3i5.717
[26]	Rolta R, Salaria D, Sharma B, et al. (2022) Methylxanthines as potential inhibitor of SARS-CoV-2: An in silico approach. Curr Pharmacol Rep 8: 149-170. https://doi.org/10.1007/s40495-021-00276-3
[27]	Batra B, Srinivasan S, Gopalakrishnan SG, et al. (2023) Molecular insights into the interaction of eighteen different variants of SARS-CoV-2 spike proteins with sixteen therapeutically important phytocompounds: in silico approach. J Biomol Struct Dyn 23: 1-28. https://doi.org/10.1080/07391102.2023.2169761
[28]	Lemkul JA, Bevan DR (2010) Assessing the stability of Alzheimer's amyloid protofibrils using molecular dynamics. J Phys Chem B 114: 1652-1660. https://doi.org/10.1021/jp9110794
[29]	Lee J, Cheng X, Swails JM, et al. (2016) CHARMM-GUI input generator for NAMD, GROMACS, AMBER, OpenMM, and CHARMM/OpenMM simulations using the CHARMM36 additive force field. J Chem Theory Comput 12: 405-413. https://doi.org/10.1021/acs.jctc.5b00935
[30]	Kumar Bhardwaj V, Purohit R, Kumar S (2021) Himalayan bioactive molecules as potential entry inhibitors for the human immunodeficiency virus. Food Chem 347: 128932. https://doi.org/10.1016/j.foodchem.2020.128932
[31]	Tanwar G, Mazumder AG, Bhardwaj V, et al. (2019) Target identification, screening and in vivo evaluation of pyrrolone-fused benzosuberene compounds against human epilepsy using Zebrafish model of pentylenetetrazol-induced seizures. Sci Rep 9: 7904. https://doi.org/10.1038/s41598-019-44264-6
[32]	Bhardwaj VK, Oakley A, Purohit R (2022) Mechanistic behavior and subtle key events during DNA clamp opening and closing in T4 bacteriophage. Int J Biol Macromol 208: 11-19. https://doi.org/10.1016/j.ijbiomac.2022.03.021
[33]	Bhardwaj V, Purohit R (2020) Computational investigation on effect of mutations in PCNA resulting in structural perturbations and inhibition of mismatch repair pathway. J Biomol Struct Dyn 38: 1963-1974. https://doi.org/10.1080/07391102.2019.1621210
[34]	Purohit R, Rajasekaran R, Sudandiradoss C, et al. (2008) Studies on flexibility and binding affinity of Asp25 of HIV-1 protease mutants. Int J Biol Macromol 42: 386-391. https://doi.org/10.1016/j.ijbiomac.2008.01.011
[35]	Kumar A, Rajendran V, Sethumadhavan R, et al. (2012) In silico prediction of a disease-associated STIL mutant and its affect on the recruitment of centromere protein J (CENPJ). FEBS Open Bio 2: 285-293. https://doi.org/10.1016/j.fob.2012.09.003
[36]	Narayanan N, Nair DT (2020) Vitamin B₁₂ may inhibit RNA-dependent-RNA polymerase activity of nsp12 from the SARS-CoV-2 virus. IUBMB Life 72: 2112-2120. https://doi.org/10.1002/iub.2359
[37]	Zhang H, Yang Y, Li J, et al. (2020) A novel virtual screening procedure identifies Pralatrexate as inhibitor of SARS-CoV-2 RdRp and it reduces viral replication in vitro. PLoS Comput Biol 16: e1008489. https://doi.org/10.1371/journal.pcbi.1008489
[38]	Shree P, Mishra P, Selvaraj C, et al. (2022) Targeting COVID-19 (SARS-CoV-2) main protease through active phytochemicals of ayurvedic medicinal plants–Withania somnifera (Ashwagandha), Tinospora cordifolia (Giloy) and Ocimum sanctum (Tulsi)—a molecular docking study. J Biomol Struct Dyn 40: 190-203. https://doi.org/10.1080/07391102.2020.1810778
[39]	Chen C, Zhang XR, Ju ZY, et al. (2020) Advances in the research of cytokine storm mechanism induced by Corona Virus Disease 2019 and the corresponding immunotherapies. Zhonghua Shao Shang Za Zhi 36: 471-475. https://doi.org/10.3760/cma.j.cn501120-20200224-00088
[40]	Elfiky AA (2020) Ribavirin, remdesivir, sofosbuvir, galidesivir, and tenofovir against SARS-CoV-2 RNA dependent RNA polymerase (RdRp): A molecular docking study. Life Sci 253: 117592. https://doi.org/10.1016/j.lfs.2020.117592
[41]	Dai W, Zhang B, Jiang XM, et al. (2020) Structure-based design of antiviral drug candidates targeting the SARS-CoV-2 main protease. Science 368: 1331-1335. https://doi.org/10.1126/science.abb4489
[42]	Dhankhar P, Dalal V, Singh V, et al. (2020) Computational guided identification of novel potent inhibitors of N-terminal domain of nucleocapsid protein of severe acute respiratory syndrome coronavirus 2. J Biomol Struct Dyn 40: 4084-4099. https://doi.org/10.1080/07391102.2020.1852968
[43]	Lan J, Ge J, Yu J (2020) Structure of the SARS-CoV-2 spike receptor-binding domain bound to the ACE₂ receptor. Nature 581: 215-220. https://doi.org/10.1038/s41586-020-2180-5
[44]	Kadioglu O, Saeed M, Greten HJ, et al. (2021) Identification of novel compounds against three targets of SARS CoV-2 coronavirus by combined virtual screening and supervised machine learning. Comput Biol Med 133: 104359. https://doi.org/10.1016/j.compbiomed.2021.104359
[45]	Mishra A, Rathore AS (2022) RNA dependent RNA polymerase (RdRp) as a drug target for SARS-CoV2. J Biomol Struct Dyn 40: 6039-6051. https://doi.org/10.1080/07391102.2021.1875886
[46]	Lee L Dengue death toll rises in Malaysia, number of cases close to double (2019). Available from: https://www.insider.com/dengue-death-toll-rises-in-malaysia-number-of-cases-close-to-double-2019-8
[47]	Sharma N, Mishra KP, Chanda S, et al. (2019) Evaluation of anti-dengue activity of Carica papaya aqueous leaf extract and its role in platelet augmentation. Arch Virol 164: 1095-1110. https://doi.org/10.1007/s00705-019-04179-z
[48]	Hettige S (2008) Salutary effects of Carica papaya leaf extract in dengue fever patients—a pilot study. Sri Lankan Family Physician 29: 17-19.
[49]	Hettige S (2017) The use of dried carica papaya leaf capsules in dengue fever patients in the recent dengue epidemic in June–August 2017. Sri Lankan Family Phys 33: 21-26.
[50]	Assir MZK, Mansoor H, Waseem T, et al. (2012) Effect of papaya leaf extract on platelet count in dengue fever: a randomized controlled trial (PLEAD Trial). Int J Infect Dis 16: E473. https://doi.org/10.1016/j.ijid.2012.05.686
[51]	Yunita F, Hanani E, Kristianto J (2012) The effect of Carica papaya L. leaves extract capsules on platelets count and hematocrit level in dengue fever patient. Int J Med Aromat Plants 2: 573-578.
[52]	Subenthiran S, Choon TC, Cheong KC, et al. (2013) Carica papaya leaves juice significantly accelerates the rate of increase in platelet count among patients with dengue fever and dengue haemorrhagic fever. Evid-Based Compl Alt Med 2013: 616737. https://doi.org/10.1155/2013/616737
[53]	Singhai A, Juneja V, Abbas S, et al. (2016) The effect of Carica papaya leaves extract capsules on platelets count and hematocrit levelsin acute febrile illness with thrombocytopenia patient. Int J Med Res Health Sci 5: 254-257.
[54]	Adarsh VB, Doddamane K, Kumar VD (2017) Role of carica papaya leaf product in improving the platelet count in patients with dengue fever. Int J Res Medi 6: 63-68.
[55]	Semwal DK, Dahiya RS, Joshi N, et al. (2018) Preclinical and clinical studies to evaluate the effect of carica papaya leaf extract on platelets. Curr Tradit Med 4: 297-304. https://doi.org/10.2174/2215083805666190124162640
[56]	Shetty D, Manoj A, Jain D, et al. (2019) The effectiveness of carica papaya leaf extract in children with dengue fever. ejbps 6: 380-383.
[57]	Srikanth BK, Reddy L, Biradar S, et al. (2019) An open-label, randomized prospective study to evaluate the efficacy and safety of Carica papaya leaf extract for thrombocytopenia associated with dengue fever in pediatric subjects. Pediatric Health Med Ther 10: 5-11. https://doi.org/10.2147/PHMT.S176712
[58]	Janagan T, Sridevi SA (2020) Pharmacoepidemiological study of the usage of caripill for the dengue patients in an urban health setup among the registered medical practitioners. IP Int J Compr Adv Pharmacol 5: 42-44. http://doi.org/10.18231/j.ijcaap.2020.010
[59]	Sathyapalan DT, Padmanabhan A, Moni M, et al. (2020) Efficacy & safety of carica papaya leaf extract (CPLE) in severe thrombocytopenia (≤ 30,000/µL) in adult dengue—Results of a pilot study. PLoS One 15: e0228699. https://doi.org/10.1371/journal.pone.0228699
[60]	Solanki SG, Trivedi P (2020) Evaluation of the efficacy of Carica papaya leaf extract on platelet counts in dengue patients. J Adv Sci Res 11: 62-65.
[61]	Karimi A, Majlesi M, Rafieian-Kopaei M (2015) Herbal versus synthetic drugs; beliefs and facts. J Nephropharmacol 4: 27-30.
[62]	Malavige GN, Jeewandara C, Ogg GS (2022) Dengue and COVID-19: Two sides of the same coin. J Biomed Sci 29: 48. https://doi.org/10.1186/s12929-022-00833-y
[63]	Favaloro EJ, Pasalic L, Lippi G (2022) Review and evolution of guidelines for diagnosis of COVID-19 vaccine induced thrombotic thrombocytopenia (VITT). Clin Chem Lab Med (CCLM) 60: 7-17. https://doi.org/10.1515/cclm-2021-1039
[64]	Mo P, Xing Y, Xiao Y, et al. (2020) Clinical characteristics of refractory COVID-19 pneumonia in Wuhan, China. Clin Infect Dis 73: e4208-e4213. https://doi.org/10.1093/cid/ciaa270
[65]	Jiang SQ, Huang QF, Xie WM, et al. (2020) The association between severe COVID-19 and low platelet count: evidence from 31 observational studies involving 7613 participants. Br J Haematol 190: e29-e33. https://doi.org/10.1111/bjh.16817
[66]	Larsen JB, Pasalic L, Hvas AM (2020) Platelets in Coronavirus disease 2019. Semin Thromb Hemost 46: 823-825. https://doi.org/10.1055/s-0040-1710006
[67]	Chuansumrit A, Chaiyaratana W (2014) Hemostatic derangement in dengue hemorrhagic fever. Thromb Res 133: 10-16. https://doi.org/10.1016/j.thromres.2013.09.028
[68]	Feldmann M, Maini RN, Woody JN, et al. (2020) Trials of anti-tumour necrosis factor therapy for COVID-19 are urgently needed. Lancet 395: 1407-1409. https://doi.org/10.1016/S0140-6736(20)30858-8
[69]	Robinson PC, Richards D, Tanner HL, et al. (2020) Accumulating evidence suggests anti-TNF therapy needs to be given trial priority in COVID-19 treatment. Lancet Rheumatol 2: e653-e655. https://doi.org/10.1016/S2665-9913(20)30309-X
[70]	Norahmad NA, Mohd Abd Razak MR, Mohmad Misnan N, et al. (2019) Effect of freeze-dried Carica papaya leaf juice on inflammatory cytokines production during dengue virus infection in AG129 mice. BMC Complement Altern Med 19: 49. https://doi.org/10.1186/s12906-019-2438-3
[71]	Binachon C Inhibiteur de TNF-alpha. FR2973705A1 (2012).
[72]	Tisoncik JR, Korth MJ, Simmons CP, et al. (2012) Into the Eye of the Cytokine Storm. Microbiol Mol Biol Rev 76: 16-32. https://doi.org/10.1128/MMBR.05015-11
[73]	Adarsh M, Abraham A, Kavitha P, et al. (2021) Severe thrombocytopenia in COVID-19: A conundrum in dengue-endemic areas. Indian J Crit Care Med 25: 465-466. https://doi.org/10.5005/jp-journals-10071-23778
[74]	Zunjar V, Dash RP, Jivrajani M, et al. (2016) Antithrombocytopenic activity of carpaine and alkaloidal extract of Carica papaya Linn. leaves in busulfan induced thrombocytopenic Wistar rats. J Ethnopharmacol 181: 20-25. https://doi.org/10.1016/j.jep.2016.01.035
[75]	Munir S, Liu ZW, Tariq T, et al. (2022) Delving into the therapeutic potential of Carica papaya leaf against thrombocytopenia. Molecules 27: 2760. https://doi.org/10.3390/molecules27092760
[76]	Shukor MS, Shukor MY Potential herbal-based treatment for COVID-19, a case for papaya leaves extract (2020). Available from: https://vixra.org/pdf/2004.0087v8.pdf
[77]	Saif R, Zafar MO, Raza MH, et al. (2020) Computational prediction of Carica papaya extracts as potential drug agents against RNA polymerase and Spike proteins of SARS-nCoV2. Res Square 1–11. https://doi.org/10.21203/rs.3.rs-105301/v1
[78]	Chen YC (2015) Beware of docking!. Trends Pharmacol Sci 36: 78-95. https://doi.org/10.1016/j.tips.2014.12.001
[79]	Yesudhas D, Srivastava A, Sekijima M, et al. (2021) Tackling Covid-19 using disordered-to-order transition of residues in the spike protein upon angiotensin-converting enzyme 2 binding. Proteins 89: 1158-1166. https://doi.org/10.1002/prot.26088
[80]	Zhang L, Lin D, Sun X, et al. (2020) Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science 368: 409-412. https://doi.org/10.1126/science.abb3405
[81]	Hu X, Zhou Z, Li F, et al. (2021) The study of antiviral drugs targeting SARS-CoV-2 nucleocapsid and spike proteins through large-scale compound repurposing. Heliyon 7: e06387. https://doi.org/10.1016/j.heliyon.2021.e06387
[82]	Suravajhala R, Parashar A, Choudhir G, et al. (2021) Molecular docking and dynamics studies of curcumin with COVID-19 proteins. Netw Model Anal Health Inform Bioinforma 10: 44. https://doi.org/10.1007/s13721-021-00312-8
[83]	Frisch MJ, Trucks GW, Schlegel HB, et al. (2016) Gaussiañ16 Revision C.01. Gaussian, Inc, Wallingford CT .
[84]	Morris GM, Huey R, Lindstrom W, et al. (2009) AutoDock₄ and AutoDockTools₄: Automated docking with selective receptor flexibility. J Comput Chem 30: 2785-2791. https://doi.org/10.1002/jcc.21256
[85]	Mehta J, Utkarsh K, Fuloria S, et al. (2022) Antibacterial potential of bacopa monnieri (L.) Wettst. and its bioactive molecules against uropathogens—An in silico study to identify potential lead molecule(s) for the development of new drugs to treat urinary tract infections. Molecules 27: 4971. https://doi.org/10.3390/molecules27154971
[86]	Baghban R, Farajnia S, Ghasemi Y, et al. (2021) Engineering of ocriplasmin variants by bioinformatics methods for the reduction of proteolytic and autolytic activities. Iran J Med Sci 46: 454-467. https://doi.org/10.30476/ijms.2020.86984.1705
[87]	Pereira RCC, Lourenço AL, Terra L, et al. (2017) Marine diterpenes: Molecular modeling of thrombin inhibitors with potential biotechnological application as an antithrombotic. Mar Drugs 15: 79. https://doi.org/10.3390/md15030079
[88]	Gapsys V, Michielssens S, Seeliger D, et al. (2015) pmx: Automated protein structure and topology generation for alchemical perturbations. J Comput Chem 36: 348-354. https://doi.org/10.1002/jcc.23804
[89]	Chakraborty B, Sengupta C, Pal U, et al. (2017) Acridone in biological nanocavity: A detailed spectroscopic and docking analyses of probing both the tryptophan residues of bovine serum albumin. New J Chem 41: 12520-12534. https://doi.org/10.1039/C7NJ02454A
[90]	Kumari R, Kumar R, Lynn A (2014) g_mmpbsa—A GROMACS tool for high-throughput MM-PBSA calculations. J Chem Inf Model 54: 1951-1962. https://doi.org/10.1021/ci500020m
[91]	Kang S, Yang M, Hong Z, et al. (2020) Crystal structure of SARS-CoV-2 nucleocapsid protein RNA binding domain reveals potential unique drug targeting sites. Acta Pharm Sin B 10: 1228-1238. https://doi.org/10.1016/j.apsb.2020.04.009
[92]	Kabinger F, Stiller C, Schmitzová J, et al. (2021) Mechanism of molnupiravir-induced SARS-CoV-2 mutagenesis. Nat Struct Mol Biol 28: 740-746. https://doi.org/10.1038/s41594-021-00651-0
[93]	Redhead MA, Owen CD, Brewitz L, et al. (2021) Bispecific repurposed medicines targeting the viral and immunological arms of COVID-19. Sci Rep 11: 13208. https://doi.org/10.1038/s41598-021-92416-4
[94]	Han P, Li L, Liu S, et al. (2022) Receptor binding and complex structures of human ACE2 to spike RBD from omicron and delta SARS-CoV-2. Cell 185: 630-640. https://doi.org/10.1016/j.cell.2022.01.001
[95]	He MM, Smith AS, Oslob JD, et al. (2005) Small-molecule inhibition of TNF-alpha. Science 310: 1022-1025. https://doi.org/10.1126/science.1116304
[96]	Yamada T, Kurihara K, Ohnishi Y, et al. (2013) Neutron and X-ray crystallographic analysis of the human α-thrombin-bivalirudin complex at pD 5.0: Protonation states and hydration structure of the enzyme-product complex. BBA–Proteins Proteom 1834: 1532-1538. https://doi.org/10.1016/j.bbapap.2013.05.014
[97]	Doak BC, Over B, Giordanetto F, et al. (2014) Oral Druggable Space beyond the Rule of 5: Insights from Drugs and Clinical Candidates. Chem Biol 21: 1115-1142. https://doi.org/10.1016/j.chembiol.2014.08.013
[98]	Machado D, Girardini M, Viveiros M, et al. (2018) Challenging the drug-likeness dogma for new drug discovery in tuberculosis. Front Microbiol 9: 1367. https://doi.org/10.3389/fmicb.2018.01367
[99]	Khan A, Tahir Khan M, Saleem S, et al. (2020) Structural insights into the mechanism of RNA recognition by the N-terminal RNA-binding domain of the SARS-CoV-2 nucleocapsid phosphoprotein. Comput Struct Biotechnol J 18: 2174-2184. https://doi.org/10.1016/j.csbj.2020.08.006
[100]	Ray M, Sarkar S, Rath SN (2020) Druggability for COVID-19: In silico discovery of potential drug compounds against nucleocapsid (N) protein of SARS-CoV-2. Genomics Inform 18: e43. https://doi.org/10.5808/GI.2020.18.4.e43
[101]	Eweas AF, Alhossary AA, Abdel-Moneim AS (2021) Molecular docking reveals ivermectin and remdesivir as potential repurposed drugs against SARS-CoV-2. Front Microbiol 11: 592908. https://doi.org/10.3389/fmicb.2020.592908
[102]	Falana M, Nurudeen Q (2020) Analysis of secondary metabolites and in vitro evaluation of extracts of Carica papaya and Azadirachta indica leaves on selected human pathogens. Notulae Scientia Biologicae 12: 57-73. https://doi.org/10.15835/nsb12110541
[103]	Razak MRMA, Misnan NM, Jelas NHM, et al. (2018) The effect of freeze-dried Carica papaya leaf juice treatment on NS1 and viremia levels in dengue fever mice model. BMC Complement Altern Med 18: 320. https://doi.org/10.1186/s12906-018-2390-7
[104]	Omar HR, Komarova I, El-Ghonemi M, et al. (2012) Licorice abuse: time to send a warning message. Ther Adv Endocrinol Metab 3: 125-138.
[105]	Rahayu SE, Leksono AS, Gama ZP, et al. (2020) The active compounds composition and antifeedant activity of leaf extract of two cultivar Carica papaya L. on Spodoptera litura F, Larvae. AIP Conf Proc 2231. https://doi.org/10.1063/5.0002677
[106]	Canini A, Alesiani D, D'Arcangelo G, et al. (2007) Gas chromatography–mass spectrometry analysis of phenolic compounds from Carica papaya L. leaf. J Food Compos Anal 20: 584-590. https://doi.org/10.1016/j.jfca.2007.03.009
[107]	Radhakrishnan N, Lam KW, Norhaizan ME (2017) Molecular docking analysis of Carica papaya Linn constituents as antiviral agent. Int Food Res J 24: 1819-1825.
[108]	Martin RJ, Robertson AP, Choudhary S (2021) Ivermectin: An Anthelmintic, an Insecticide, and Much More. Trends Parasitol 37: 48-64. https://doi.org/10.1016/j.pt.2020.10.005
[109]	Adegbola PI, Semire B, Fadahunsi OS, et al. (2021) Molecular docking and ADMET studies of Allium cepa, Azadirachta indica and Xylopia aethiopica isolates as potential anti-viral drugs for Covid-19. VirusDis 32: 85-97. https://doi.org/10.1007/s13337-021-00682-7
[110]	Nagar PR, Gajjar ND, Dhameliya TM (2021) In search of SARS CoV-2 replication inhibitors: Virtual screening, molecular dynamics simulations and ADMET analysis. J Mol Struct 1246: 131190. https://doi.org/10.1016/j.molstruc.2021.131190
[111]	Ayipo YO, Ahmad I, Najib YS, et al. (2022) Molecular modelling and structure-activity relationship of a natural derivative of o-hydroxybenzoate as a potent inhibitor of dual NSP3 and NSP12 of SARS-CoV-2: In silico study. J Biomol Struct Dyn 41: 1959-1977. https://doi.org/10.1080/07391102.2022.2026818
[112]	Elkarhat Z, Charoute H, Elkhattabi L, et al. (2022) Potential inhibitors of SARS-cov-2 RNA dependent RNA polymerase protein: molecular docking, molecular dynamics simulations and MM-PBSA analyses. J Biomol Struct Dyn 40: 361-374. https://doi.org/10.1080/07391102.2020.1813628
[113]	de Leon VN, Manzano JAH, Pilapil DYH, et al. Repurposing multi-targeting plant natural product scaffolds in silico against SARS-CoV-2 non-structural proteins implicated in viral pathogenesis (2021). https://doi.org/10.26434/chemrxiv.14125433.v1
[114]	Wang B, Svetlov V, Wolf YI, et al. (2021) Allosteric activation of SARS-CoV-2 RNA-dependent RNA polymerase by remdesivir triphosphate and other phosphorylated nucleotides. mBio 12: e0142321. https://doi.org/10.1101/2021.01.24.428004
[115]	Peng L, Tian X, Shen L, et al. (2020) Identifying effective antiviral drugs against SARS-CoV-2 by drug repositioning through virus-drug association prediction. Front Genet 11: 577387. https://doi.org/10.3389/fgene.2020.577387
[116]	Balkrishna A, Mittal R, Arya V (2021) Computational evidences of phytochemical mediated disruption of pLpro driven replication of SARS-CoV-2: A therapeutic approach against COVID-19. Curr Pharm Biotechnol 22: 1350-1359. https://doi.org/10.2174/1389201021999201110204116
[117]	Nugroho A, Heryani H, Choi JS (2017) Identification and quantification of flavonoids in Carica papaya leaf and peroxynitrite-scavenging activity. Asian Pac J Trop Bio 7: 208-213. https://doi.org/10.1016/j.apjtb.2016.12.009
[118]	Kresge N, Simoni RD, Hill RL (2005) Hemorrhagic Sweet Clover Disease, Dicumarol, and Warfarin: The Work of Karl Paul Link. J Biol Chem 280: e6-e7. https://doi.org/10.1016/S0021-9258(19)62862-0
[119]	Caly L, Druce JD, Catton MG, et al. (2020) The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro. Antivir Res 178: 104787. https://doi.org/10.1016/j.antiviral.2020.104787
[120]	Elekofehinti OO, Iwaloye O, Famusiwa CD, et al. (2021) Identification of main protease of coronavirus SARS-CoV-2 (Mpro) inhibitors from Melissa officinalis. Curr Drug Discov Technol 18: e17092020186048. https://doi.org/10.2174/1570163817999200918103705
[121]	Mahmoud A, Mostafa A, Al-Karmalawy AA, et al. (2021) Telaprevir is a potential drug for repurposing against SARS-CoV-2: computational and in vitro studies. Heliyon 7: e07962. https://doi.org/10.1016/j.heliyon.2021.e07962
[122]	Bzówka M, Mitusińska K, Raczyńska A, et al. (2020) Structural and evolutionary analysis indicate that the SARS-CoV-2 Mpro is a challenging target for small-molecule inhibitor design. Int J Mol Sci 21: 3099. https://doi.org/10.3390/ijms21093099
[123]	Jin Z, Du X, Xu Y, et al. (2020) Structure of M^pro from SARS-CoV-2 and discovery of its inhibitors. Nature 582: 289-293. https://doi.org/10.1038/s41586-020-2223-y
[124]	Owen DR, Allerton CMN, Anderson AS, et al. (2021) An oral SARS-CoV-2 Mpro inhibitor clinical candidate for the treatment of COVID-19. Science 374: 1586-1593.
[125]	Yu W, Wu X, Zhao Y, et al. (2021) Computational simulation of HIV protease inhibitors to the main protease (Mpro) of SARS-CoV-2: Implications for COVID-19 drugs design. Molecules 26: 7385. https://doi.org/10.3390/molecules26237385
[126]	Khor B -K., Chear NJ -Y., Azizi J, et al. (2021) Chemical composition, antioxidant and cytoprotective potentials of Carica papaya leaf extracts: A comparison of supercritical fluid and conventional extraction methods. Molecules 26: 1489. https://doi.org/10.3390/molecules26051489
[127]	Anjum V, Arora P, Ansari SH, et al. (2017) Antithrombocytopenic and immunomodulatory potential of metabolically characterized aqueous extract of Carica papaya leaves. Pharm Biol 55: 2043-2056. https://doi.org/10.1080/13880209.2017.1346690
[128]	Wrapp D, Wang N, Corbett KS, et al. (2020) Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science 367: 1260-1263. https://doi.org/10.1126/science.abb2507
[129]	Candelli M, Rossi E, Valletta F, et al. (2021) Immune thrombocytopenic purpura after SARS-CoV-2 vaccine. Br J Haematol 194: 547-549. https://doi.org/10.1111/bjh.17508
[130]	Kircheis R (2021) Coagulopathies after vaccination against SARS-CoV-2 may be derived from a combined effect of SARS-CoV-2 spike protein and adenovirus vector-triggered signaling pathways. Int J Mol Sci 22: 10791. https://doi.org/10.3390/ijms221910791
[131]	Theoharides TC, Conti P (2021) Be aware of SARS-CoV-2 spike protein: There is more than meets the eye. J Biol Regul Homeost Agents 35: 833-838. https://doi.org/10.23812/THEO_EDIT_3_21
[132]	Wise J (2021) Covid-19: European countries suspend use of Oxford-AstraZeneca vaccine after reports of blood clots. BMJ 372: n699. https://doi.org/10.1136/bmj.n699
[133]	Banks WA, Erickson MA (2022) The next chapter for COVID-19: A respiratory virus inflames the brain. Brain Behav Immun 101: 286-287. https://doi.org/10.1016/j.bbi.2022.01.017
[134]	Caohuy H, Eidelman O, Chen T, et al. Inflammation in the COVID-19 airway is due to inhibition of CFTR signaling by the SARS-CoV-2 Spike protein (2022)2022:. https://doi.org/10.1101/2022.01.18.476803
[135]	Nugent MA (2022) The future of the COVID-19 pandemic: How good (or bad) can the SARS-CoV2 Spike protein get?. Cells 11: 855. https://doi.org/10.3390/cells11050855
[136]	Theoharides TC (2022) Could SARS-CoV-2 Spike protein be responsible for long-COVID syndrome?. Mol Neurobiol 59: 1850-1861. https://doi.org/10.1007/s12035-021-02696-0
[137]	Sakkiah S, Guo W, Pan B (2021) Elucidating interactions between SARS-CoV-2 trimeric Spike protein and ACE2 using homology modeling and molecular dynamics simulations. Front Chem 8: 622632. https://doi.org/10.3389/fchem.2020.622632
[138]	Entzminger KC, Fleming JK, Entzminger PD, et al. (2023) Rapid engineering of SARS-CoV-2 therapeutic antibodies to increase breadth of neutralization including BQ.1.1, CA.3.1, CH.1.1, XBB.1.16, and XBB.1.5. Antib Ther 6: 108-118. https://doi.org/10.1093/abt/tbad006
[139]	Wu L, Zhou L, Mo M, et al. (2022) SARS-CoV-2 Omicron RBD shows weaker binding affinity than the currently dominant Delta variant to human ACE2. Sig Transduct Target Ther 7: 8. https://doi.org/10.1038/s41392-021-00863-2
[140]	Bennett RN, Kiddle G, Wallsgrove RM (1997) Biosynthesis of benzylglucosinolate, cyanogenic glucosides and phenylpropanoids in Carica papaya. Phytochemistry 45: 59-66. https://doi.org/10.1016/S0031-9422(96)00787-X
[141]	He MM, Smith AS, Oslob JD, et al. (2005) Small-molecule inhibition of TNF-α. Science 310: 1022-1025. https://doi.org/10.1126/science.1116304
[142]	Zia K, Ashraf S, Jabeen A, et al. (2020) Identification of potential TNF-α inhibitors: from in silico to in vitro studies. Sci Rep 10: 20974. https://doi.org/10.1038/s41598-020-77750-3
[143]	Yoshikawa M, Toyohara M, Ueda S, et al. (1999) Glycyrrhizin inhibits TNF-induced, but not Fas-mediated, apoptosis in the human hepatoblastoma line HepG2. Biol Pharm Bull 22: 951-955. https://doi.org/10.1248/bpb.22.951
[144]	Wang YM, Du GQ (2016) Glycyrrhizic acid prevents enteritis through reduction of NF‑κB p65 and p38MAPK expression in rat. Mol Med Rep 13: 3639-3646. https://doi.org/10.3892/mmr.2016.4981
[145]	Boyenle ID, Adelusi TI, Ogunlana AT, et al. (2022) Consensus scoring-based virtual screening and molecular dynamics simulation of some TNF-alpha inhibitors. Inform Med Unlocked 28: 100833. https://doi.org/10.1016/j.imu.2021.100833
[146]	Becher Y, Goldman L, Schacham N, et al. (2020) D-dimer and C-reactive protein blood levels over time used to predict pulmonary embolism in two COVID-19 patients. Eur J Case Rep Intern Med 7: 001725. https://doi.org/10.12890/2020_001725
[147]	Chi Y, Ge Y, Wu B, et al. (2020) Serum cytokine and chemokine profile in relation to the severity of coronavirus disease 2019 in China. J Infect Dis 222: 746-754. https://doi.org/10.1093/infdis/jiaa363
[148]	Porfidia A, Pola R (2020) Venous thromboembolism in COVID-19 patients. J Thromb Haemost 18: 1516-1517. https://doi.org/10.1111/jth.14842
[149]	Porres-Aguilar M, Torres-Machorro A, Aurón M (2020) Trombólisis en niños con tromboembolia pulmonar asociada a COVID-19. Gac Med Mex 156: 618-618.
[150]	Schulman S, Hu Y, Konstantinides S (2020) Venous thromboembolism in COVID-19. Thromb Haemost 120: 1642-1653. https://doi.org/10.1055/s-0040-1718532
[151]	Tang N, Li D, Wang X, et al. (2020) Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 18: 844-847. https://doi.org/10.1111/jth.14768
[152]	Aydın FY, Demircan V (2021) Diagnosis and management of coronavirus disease-associated immune thrombocytopenia: a case series. Rev Soc Bras Med Trop 54: e0029. https://doi.org/10.1590/0037-8682-0029-2021
[153]	Pranata R, Lim MA, Yonas E, et al. (2021) Thrombocytopenia as a prognostic marker in COVID-19 patients: diagnostic test accuracy meta-analysis. Epidemiol Infect 149: e40. https://doi.org/10.1017/S0950268821000236
[154]	Perreau M, Suffiotti M, Marques-Vidal P, et al. (2021) The cytokines HGF and CXCL13 predict the severity and the mortality in COVID-19 patients. Nat Commun 12: 4888. https://doi.org/10.1038/s41467-021-25191-5
[155]	Parves MR, Mahmud S, Riza YM, et al. (2020) Inhibition of TNF-alpha using plant-derived small molecules for treatment of inflammation-mediated diseases. Proceedings 79: 13. https://doi.org/10.3390/IECBM2020-08586
[156]	Paidi RK, Jana M, Raha S, et al. (2021) Eugenol, a component of Holy Basil (Tulsi) and common spice clove, inhibits the interaction between SARS-CoV-2 Spike S1 and ACE2 to induce therapeutic responses. J Neuroimmune Pharmacol 16: 743-755. https://doi.org/10.1007/s11481-021-10028-1
[157]	Junqueira C, Crespo Â, Ranjbar S, et al. (2022) FcγR-mediated SARS-CoV-2 infection of monocytes activates inflammation. Nature 606: 576-584. https://doi.org/10.1038/s41586-022-04702-4
[158]	Bode W, Turk D, Karshikov A (1992) The refined 1.9-A X-ray crystal structure of D-Phe-Pro-Arg chloromethylketone-inhibited human alpha-thrombin: structure analysis, overall structure, electrostatic properties, detailed active-site geometry, and structure-function relationships. Protein Sci 1: 426-471. https://doi.org/10.1002/pro.5560010402
[159]	Hartley BS (1970) Homologies in serine proteinases. Phil Trans R Soc Lond B 257: 77-87. https://doi.org/10.1098/rstb.1970.0010
[160]	Mauricio I, Francischetti B, Monteiro RQ, et al. (1997) Identification of glycyrrhizin as a thrombin inhibitor. Biochem Biophys Res Commun 235: 259-263. https://doi.org/10.1006/bbrc.1997.6735
[161]	Mendes-Silva W, Assafim M, Ruta B, et al. (2003) Antithrombotic effect of Glycyrrhizin, a plant-derived thrombin inhibitor. Thromb Res 112: 93-98. https://doi.org/10.1016/j.thromres.2003.10.014
[162]	Zhou P, Huang JL (2020) Prediction of material foundation of Ling-Gui-Zhu-Gan decoction for chronic heart failure based on molecular docking. Pak J Pharm Sci 33: 1459-1464.
[163]	Yu X, Wei LH, Zhang JK, et al. (2019) Anthraquinones from Cassiae semen as thrombin inhibitors: in vitro and in silico studies. Phytochemistry 165: 112025. https://doi.org/10.1016/j.phytochem.2019.04.018
[164]	Alam W (2021) COVID-19 vaccine-induced immune thrombotic thrombocytopenia: A review of the potential mechanisms and proposed management. Sci Prog 104: 368504211025927. https://doi.org/10.1177/00368504211025927
[165]	Ganzel C, Ben-Chetrit E (2021) Immune Thrombocytopenia Following the Pfizer-BioNTech BNT162b2 mRNA COVID-19 Vaccine. Isr Med Assoc J 23: 341.
[166]	Garnier M, Curado A, Billoir P, et al. (2021) Imaging of Oxford/AstraZeneca® COVID-19 vaccine-induced immune thrombotic thrombocytopenia. Diagn Interv Imaging 102: 649-650. https://doi.org/10.1016/j.diii.2021.04.005
[167]	Gupta A, Sardar P, Cash ME, et al. (2021) Covid-19 vaccine—induced thrombosis and thrombocytopenia-a commentary on an important and practical clinical dilemma. Prog Cardiovasc Dis 67: 105-107. https://doi.org/10.1016/j.pcad.2021.05.001
[168]	Malik B, Kalantary A, Rikabi K, et al. (2021) Pulmonary embolism, transient ischaemic attack and thrombocytopenia after the Johnson & Johnson COVID-19 vaccine. BMJ Case Rep 14: e243975. https://doi.org/10.1136/bcr-2021-243975
[169]	Novak N, Tordesillas L, Cabanillas B (2021) Adverse rare events to vaccines for COVID-19: From hypersensitivity reactions to thrombosis and thrombocytopenia. Int Rev Immunol 41: 438-447. https://doi.org/10.1080/08830185.2021.1939696
[170]	Porres-Aguilar M, Lazo-Langner A, Panduro A, et al. (2021) COVID-19 vaccine-induced immune thrombotic thrombocytopenia: An emerging cause of splanchnic vein thrombosis. Ann Hepatol 23: 100356. https://doi.org/10.1016/j.aohep.2021.100356
[171]	Scharf RE, Alberio L (2021) COVID-19: SARS-CoV-2 vaccine-induced immune thrombotic thrombocytopenia. Hamostaseologie 41: 179-182. https://doi.org/10.1055/a-1369-3488
[172]	Toom S, Wolf B, Avula A, et al. (2021) Familial thrombocytopenia flare-up following the first dose of mRNA-1273 Covid-19 vaccine. Am J Hematol 96: E134-E135. https://doi.org/10.1002/ajh.26128
[173]	Welsh KJ, Baumblatt J, Chege W, et al. (2021) Thrombocytopenia including immune thrombocytopenia after receipt of mRNA COVID-19 vaccines reported to the Vaccine Adverse Event Reporting System (VAERS). Vaccine 39: 3329-3332. https://doi.org/10.1016/j.vaccine.2021.04.054
[174]	Chaves OA, Sacramento CQ, Fintelman-Rodrigues N, et al. (2021) Apixaban, an orally available anticoagulant, inhibits SARS-CoV-2 replication by targeting its major protease in a non-competitive way. J Mol Cell Biol 14: mjac039. https://doi.org/10.1093/jmcb/mjac039
[175]	Morishima Y, Shibutani T, Noguchi K, et al. (2021) Edoxaban, a direct oral factor Xa inhibitor, ameliorates coagulation, microvascular thrombus formation, and acute liver injury in a lipopolysaccharide-induced coagulopathy model in rats. J Thromb Thrombolysis 52: 9-17. https://doi.org/10.1007/s11239-021-02381-y
[176]	Cavasotto CN (2020) Binding free energy calculation using quantum mechanics aimed for drug lead optimization. Methods Mol Biol 2114: 257-268. https://doi.org/10.1007/978-1-0716-0282-9_16
[177]	El-Demerdash A, Al-Karmalawy AA, Abdel-Aziz TM, et al. (2021) Investigating the structure–activity relationship of marine natural polyketides as promising SARS-CoV-2 main protease inhibitors. RSC Adv 11: 31339-31363. https://doi.org/10.1039/d1ra05817g
[178]	Cruz JN, Silva SG, Pereira DS, et al. (2022) In silico evaluation of the antimicrobial activity of thymol—major compounds in the essential oil of Lippia thymoides Mart. & Schauer (Verbenaceae). Molecules 27: 4768. https://doi.org/10.3390/molecules27154768
[179]	Kroemer RT, Vulpetti A, McDonald JJ, et al. (2004) Assessment of docking poses: Interactions-Based Accuracy Classification (IBAC) versus crystal structure deviations. J Chem Inf Comput Sci 44: 871-881. https://doi.org/10.1021/ci049970m
[180]	Cole JC, Murray CW, Nissink JWM, et al. (2005) Comparing protein-ligand docking programs is difficult. Proteins 60: 325-332. https://doi.org/10.1002/prot.20497
[181]	Rueda M, Abagyan R (2016) Best practices in docking and activity prediction. bioRxiv : 039446. https://doi.org/10.1101/039446
[182]	Abo Elmaaty A, Alnajjar R, Hamed MIA, et al. (2021) Revisiting activity of some glucocorticoids as a potential inhibitor of SARS-CoV-2 main protease: Theoretical study. RSC Adv 11: 10027-10042. https://doi.org/10.1039/d0ra10674g
[183]	Al-Karmalawy A, Alnajjar R, Dahab MM, et al. (2021) Molecular docking and dynamics simulations reveal the potential of anti-HCV drugs to inhibit COVID-19 main protease. Pharm Sci 27: S109-S121. https://doi.org/10.34172/PS.2021.3
[184]	Alnajjar R, Mohamed N, Kawafi N (2021) Bicyclo[1.1.1]Pentane as phenyl substituent in atorvastatin drug to improve physicochemical properties: Drug-likeness, DFT, pharmacokinetics, docking, and molecular dynamic simulation. J Mol Struct 1230: 129628. https://doi.org/10.1016/j.molstruc.2020.129628
[185]	Han D, Wang H, Wujieti B, et al. (2021) Insight into the drug resistance mechanisms of GS-9669 caused by mutations of HCV NS5B polymerase via molecular simulation. Comput Struct Biotechnol J 19: 2761-2774. https://doi.org/10.1016/j.csbj.2021.04.026
[186]	Isley WC, Urick AK, Pomerantz WCK, et al. (2016) Prediction of (19)F NMR chemical shifts in labeled proteins: Computational protocol and case study. Mol Pharm 13: 2376-2386. https://doi.org/10.1021/acs.molpharmaceut.6b00137
[187]	Rolta R, Yadav R, Salaria D, et al. (2020) In silico screening of hundred phytocompounds of ten medicinal plants as potential inhibitors of nucleocapsid phosphoprotein of COVID-19: An approach to prevent virus assembly. J Biomol Struct Dyn 39: 7017-7034. https://doi.org/10.1080/07391102.2020.1804457
[188]	Amin M, Abbas G (2021) Docking study of chloroquine and hydroxychloroquine interaction with RNA binding domain of nucleocapsid phospho-protein—an in silico insight into the comparative efficacy of repurposing antiviral drugs. J Biomol Struct Dyn 39: 4243-4255. https://doi.org/10.1080/07391102.2020.1775703
[189]	Fayyazi N, Mostashari-Rad T, Ghasemi JB, et al. (2021) Molecular dynamics simulation, 3D-pharmacophore and scaffold hopping analysis in the design of multi-target drugs to inhibit potential targets of COVID-19. J Biomol Struct Dyn 40: 11787-11808. https://doi.org/10.1080/07391102.2021.1965914
[190]	Tatar G, Ozyurt E, Turhan K (2021) Computational drug repurposing study of the RNA binding domain of SARS-CoV-2 nucleocapsid protein with antiviral agents. Biotechnol Prog 37: e3110. https://doi.org/10.1002/btpr.3110
[191]	Yadav R, Imran M, Dhamija P, et al. (2021) Virtual screening and dynamics of potential inhibitors targeting RNA binding domain of nucleocapsid phosphoprotein from SARS-CoV-2. J Biomol Struct Dyn 39: 4433-4448. https://doi.org/10.1080/07391102.2020.1778536
[192]	Shirvanyants D, Ramachandran S, Mei Y, et al. (2014) Pore dynamics and conductance of RyR1 transmembrane domain. Biophys J 106: 2375-2384. https://doi.org/10.1016/j.bpj.2014.04.023
[193]	Gesto D, Cerqueira NMFSA, Ramos MJ, et al. (2014) Discovery of new druggable sites in the anti-cholesterol target HMG-CoA reductase by computational alanine scanning mutagenesis. J Mol Model 20: 2178. https://doi.org/10.1007/s00894-014-2178-8
[194]	Zhu L, Gong Y, Lju H, et al. (2021) Mechanisms of melatonin binding and destabilizing the protofilament and filament of tau R3–R4 domains revealed by molecular dynamics simulation. Phys Chem Chem Phys 23: 20615-20626. https://doi.org/10.1039/d1cp03142b
[195]	Ozcan O, Uyar A, Doruker P, et al. (2013) Effect of Intracellular Loop 3 on Intrinsic Dynamics of Human β2-Adrenergic Receptor. BMC Struct Biol 13: 29. https://doi.org/10.1186/1472-6807-13-29
[196]	Matsuo T (2021) Viewing SARS-CoV-2 nucleocapsid protein in terms of molecular flexibility. Biology (Basel) 10: 454. https://doi.org/10.3390/biology10060454
[197]	Gordon CJ, Tchesnokov EP, Woolner E, et al. (2020) Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency. J Biol Chem 295: 6785-6797. https://doi.org/10.1074/jbc.RA120.013679
[198]	Mahmud S, Biswas S, Paul GK, et al. (2021) Plant-based phytochemical screening by targeting main protease of SARS-CoV-2 to design effective potent inhibitors. Biology (Basel) 10: 589. https://doi.org/10.3390/biology10070589
[199]	Arooj M, Shehadi I, Nassab CN, et al. (2022) Computational insights into binding mechanism of drugs as potential inhibitors against SARS-CoV-2 targets. Chem Zvesti 76: 111-121. https://doi.org/10.1007/s11696-021-01843-0
[200]	Bhattacharjee S, Bhattacharyya R, Sengupta J (2021) Dynamics and electrostatics define an allosteric druggable site within the receptor-binding domain of SARS-CoV-2 spike protein. FEBS Lett 595: 442-451. https://doi.org/10.1002/1873-3468.14038
[201]	Kern P, Hemmer CJ, Damme JV, et al. (1989) Elevated tumor necrosis factor alpha and interleukin-6 serum levels as markers for complicated plasmodium falciparum malaria. Am J Med 87: 139-143. https://doi.org/10.1016/s0002-9343(89)80688-6
[202]	Danlos FX, Ackermann F, Rohmer J, et al. (2021) High levels of TNFα in patients with COVID-19 refractory to tocilizumab. Eur J Cancer 149: 102-104. https://doi.org/10.1016/j.ejca.2021.01.056
[203]	Halim SA, Sikandari AG, Khan A, et al. (2021) Structure-based virtual screening of tumor necrosis factor-α inhibitors by cheminformatics approaches and bio-molecular simulation. Biomolecules 11: 329. https://doi.org/10.3390/biom11020329
[204]	Fernández PV, Quintana I, Cerezo AS, et al. (2013) Anticoagulant activity of a unique sulfated pyranosic (1→3)-β-l-arabinan through direct interaction with thrombin. J Biol Chem 288: 223-233. https://doi.org/10.1074/jbc.M112.386441
[205]	Likić VA, Gooley PR, Speed TP, et al. (2005) A statistical approach to the interpretation of molecular dynamics simulations of calmodulin equilibrium dynamics. Protein Sci 14: 2955-2963. https://doi.org/10.1110/ps.051681605
[206]	Hu K, Yao X (2002) Protodioscin (NSC-698 796): Its spectrum of cytotoxicity against sixty human cancer cell lines in an anticancer drug screen panel. Planta Med 68: 297-301. https://doi.org/10.1055/s-2002-26743
[207]	Shen J, Yang X, Meng Z, et al. (2016) Protodioscin ameliorates fructose-induced renal injury via inhibition of the mitogen activated protein kinase pathway. Phytomedicine 23: 1504-1510. https://doi.org/10.1016/j.phymed.2016.08.009
[208]	Zhang X, Xue X, Xian L, et al. (2016) Potential neuroprotection of protodioscin against cerebral ischemia-reperfusion injury in rats through intervening inflammation and apoptosis. Steroids 113: 52-63. https://doi.org/10.1016/j.steroids.2016.06.008
[209]	Oyama M, Tokiwano T, Kawaii S, et al. (2017) Protodioscin, isolated from the rhizome of dioscorea tokoro collected in northern Japan is the major antiproliferative compound to HL-60 leukemic cells. Curr Bioact Compd 13: 170-174. https://doi.org/10.2174/1573407213666170113123428
[210]	Bagchi D, Swaroop A, Maheshwari A, et al. (2017) A novel protodioscin-enriched fenugreek seed extract (Trigonella foenum-graecum, family Fabaceae) improves free testosterone level and sperm profile in healthy volunteers. Funct Foods Health Dis 7: 235-245. https://doi.org/10.31989/ffhd.v7i4.326
[211]	Wu J, Zhao YM, Deng ZK (2018) Neuroprotective action and mechanistic evaluation of protodioscin against rat model of Parkinson's disease. Pharmacol Rep 70: 139-145. https://doi.org/10.1016/j.pharep.2017.08.013
[212]	Harmayani E, Anal AK, Wichienchot S, et al. (2019) Healthy food traditions of Asia: exploratory case studies from Indonesia, Thailand, Malaysia, and Nepal. J Ethn Food 6: 1. https://doi.org/10.1186/s42779-019-0002-x
[213]	Tietze HW (2006) Papaya the medicine tree.Harald Tietze Publishing.

molsci-10-03-015-s001.pdf

Reader Comments

Your name:*

Email:*
© 2023 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)