All Studies Meta Analysis Recent:

A computational study on hydroxychloroquine binding to target proteins related to SARS-COV-2 infection

Navya et al., Informatics in Medicine Unlocked, doi:10.1016/j.imu.2021.100714

Aug 2021

Post
Facebook

Source PDF All Studies Meta AnalysisMeta

HCQ for COVID-19

1st treatment shown to reduce risk in March 2020

^*, now known with p < 0.00000000001 from 422 studies, recognized in 42 countries.

Lower risk for mortality, hospitalization, recovery, cases, and viral clearance.

No treatment is 100% effective. Protocols combine complementary and synergistic treatments. ^* >10% efficacy in meta analysis with ≥3 clinical studies.

4,100+ studies for 60+ treatments. c19hcq.org

In Silico analysis showing that HCQ binds to multiple targets related to SARS-CoV-2 infection, including the ACE2 receptor, α7 nicotinic acetylcholine receptor, α1D-adrenergic receptor, and topoisomerase III β, suggesting that HCQ may interfere with viral entry, replication, and inflammation through interactions with these targets. Results support action of HCQ both at the entry and post-entry stages of SARS-CoV2 infection.

31 preclinical studies support the efficacy of HCQ for COVID-19:

8 In Silico studies Alkafaas, Baildya, González-Paz, Hussein, Navya, Noureddine, Tarek, Yadav

2 In Vivo animal studies Shu-Han Lin, Wen

Important missing comments or errors? Let us know.

1. Alkafaas et al., A study on the effect of natural products against the transmission of B.1.1.529 Omicron, Virology Journal, doi:10.1186/s12985-023-02160-6.biomedcentral.com, doi.org.

2. Alsmadi et al., The In Vitro, In Vivo, and PBPK Evaluation of a Novel Lung-Targeted Cardiac-Safe Hydroxychloroquine Inhalation Aerogel, AAPS PharmSciTech, doi:10.1208/s12249-023-02627-3.springer.com, doi.org.

3. Andreani et al., In vitro testing of combined hydroxychloroquine and azithromycin on SARS-CoV-2 shows synergistic effect, Microbial Pathogenesis, doi:/10.1016/j.micpath.2020.104228.sciencedirect.com, doi.org.

4. Baildya et al., Inhibitory capacity of Chloroquine against SARS-COV-2 by effective binding with Angiotensin converting enzyme-2 receptor: An insight from molecular docking and MD-simulation studies, Journal of Molecular Structure, doi:10.1016/j.molstruc.2021.129891.sciencedirect.com, doi.org.

5. Clementi et al., Combined Prophylactic and Therapeutic Use Maximizes Hydroxychloroquine Anti-SARS-CoV-2 Effects in vitro, Front. Microbiol., 10 July 2020, doi:10.3389/fmicb.2020.01704.frontiersin.org, doi.org.

6. Dang et al., Structural basis of anti-SARS-CoV-2 activity of hydroxychloroquine: specific binding to NTD/CTD and disruption of LLPS of N protein, bioRxiv, doi:10.1101/2021.03.16.435741.biorxiv.org, doi.org.

7. Delandre et al., Antiviral Activity of Repurposing Ivermectin against a Panel of 30 Clinical SARS-CoV-2 Strains Belonging to 14 Variants, Pharmaceuticals, doi:10.3390/ph15040445.mdpi.com, doi.org.

8. Faísca et al., Enhanced In Vitro Antiviral Activity of Hydroxychloroquine Ionic Liquids against SARS-CoV-2, Pharmaceutics, doi:10.3390/pharmaceutics14040877.mdpi.com, doi.org.

9. González-Paz et al., Biophysical Analysis of Potential Inhibitors of SARS-CoV-2 Cell Recognition and Their Effect on Viral Dynamics in Different Cell Types: A Computational Prediction from In Vitro Experimental Data, ACS Omega, doi:10.1021/acsomega.3c06968.acs.org, doi.org.

10. Hussein et al., Molecular Docking Identification for the efficacy of Some Zinc Complexes with Chloroquine and Hydroxychloroquine against Main Protease of COVID-19, Journal of Molecular Structure, doi:10.1016/j.molstruc.2021.129979.sciencedirect.com, doi.org.

11. Kamga Kapchoup et al., In vitro effect of hydroxychloroquine on pluripotent stem cells and their cardiomyocytes derivatives, Frontiers in Pharmacology, doi:10.3389/fphar.2023.1128382.frontiersin.org, doi.org.

12. Liu et al., Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discovery 6, 16 (2020), doi:10.1038/s41421-020-0156-0.nature.com, doi.org.

13. Miao et al., SIM imaging resolves endocytosis of SARS-CoV-2 spike RBD in living cells, Cell Chemical Biology, doi:10.1016/j.chembiol.2023.02.001.sciencedirect.com, doi.org.

14. Milan Bonotto et al., Cathepsin inhibitors nitroxoline and its derivatives inhibit SARS-CoV-2 infection, Antiviral Research, doi:10.1016/j.antiviral.2023.105655.sciencedirect.com, doi.org.

15. Mohd Abd Razak et al., In Vitro Anti-SARS-CoV-2 Activities of Curcumin and Selected Phenolic Compounds, Natural Product Communications, doi:10.1177/1934578X231188861.sagepub.com, doi.org.

16. Navya et al., A computational study on hydroxychloroquine binding to target proteins related to SARS-COV-2 infection, Informatics in Medicine Unlocked, doi:10.1016/j.imu.2021.100714.sciencedirect.com, doi.org.

17. Noureddine et al., Quantum chemical studies on molecular structure, AIM, ELF, RDG and antiviral activities of hybrid hydroxychloroquine in the treatment of COVID-19: molecular docking and DFT calculations, Journal of King Saud University - Science, doi:10.1016/j.jksus.2020.101334.sciencedirect.com, doi.org.

18. Ou et al., Hydroxychloroquine-mediated inhibition of SARS-CoV-2 entry is attenuated by TMPRSS2, PLOS Pathogens, doi:10.1371/journal.ppat.1009212.plos.org, doi.org.

19. Purwati et al., An in vitro study of dual drug combinations of anti-viral agents, antibiotics, and/or hydroxychloroquine against the SARS-CoV-2 virus isolated from hospitalized patients in Surabaya, Indonesia, PLOS One, doi:10.1371/journal.pone.0252302.plos.org, doi.org.

20. Shang et al., Inhibitors of endosomal acidification suppress SARS-CoV-2 replication and relieve viral pneumonia in hACE2 transgenic mice, Virology Journal, doi:10.1186/s12985-021-01515-1.biomedcentral.com, doi.org.

21. Sheaff, R., A New Model of SARS-CoV-2 Infection Based on (Hydroxy)Chloroquine Activity, bioRxiv, doi:10.1101/2020.08.02.232892.biorxiv.org, doi.org.

22. Shu-Han Lin et al., Inhalable Chitosan-Based Hydrogel as a Mucosal Adjuvant for Hydroxychloroquine in the Treatment for SARS-CoV-2 Infection in a Hamster Model, Journal of Microbiology, Immunology and Infection, doi:10.1016/j.jmii.2023.08.001.sciencedirect.com, doi.org.

23. Tarek et al., Pharmacokinetic Basis of the Hydroxychloroquine Response in COVID-19: Implications for Therapy and Prevention, European Journal of Drug Metabolism and Pharmacokinetics, doi:10.1007/s13318-020-00640-6.springer.com, doi.org.

24. Wang et al., Chloroquine and hydroxychloroquine as ACE2 blockers to inhibit viropexis of 2019-nCoV Spike pseudotyped virus, Phytomedicine, doi:10.1016/j.phymed.2020.153333.nih.gov, doi.org.

25. Wang (B) et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res. 30, 269–271, doi:L10.1038/s41422-020-0282-0.nature.com, doi.org.

26. Wen et al., Cholinergic α7 nAChR signaling suppresses SARS-CoV-2 infection and inflammation in lung epithelial cells, Journal of Molecular Cell Biology, doi:10.1093/jmcb/mjad048.oup.com, doi.org.

27. Yadav et al., Repurposing the Combination Drug of Favipiravir, Hydroxychloroquine and Oseltamivir as a Potential Inhibitor Against SARS-CoV-2: A Computational Study, Research Square, doi:10.21203/rs.3.rs-628277/v1.researchsquare.com, doi.org.

28. Yao et al., In Vitro Antiviral Activity and Projection of Optimized Dosing Design of Hydroxychloroquine for the Treatment of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), Clin. Infect. Dis., 2020 Mar 9, doi:10.1093/cid/ciaa237.oup.com, doi.org.

29. Yuan et al., Hydroxychloroquine blocks SARS-CoV-2 entry into the endocytic pathway in mammalian cell culture, Communications Biology, doi:10.1038/s42003-022-03841-8.nature.com, doi.org.

Navya et al., 23 Aug 2021, peer-reviewed, 2 authors. Contact: hosurmv@nias.res.in.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

This Paper HCQ All

A computational study on hydroxychloroquine binding to target proteins related to SARS-COV-2 infection

V B Navya, M V Hosur

Informatics in Medicine Unlocked, doi:10.1016/j.imu.2021.100714

Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre -including this research content -immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

Declaration of competing interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi. org/10.1016/j.imu.2021.100714.

References

Abraham, Murtola, Schulz, Páll, Smith et al., Gromacs: high performance molecular simulations through multi-level parallelism from laptops to supercomputers, SoftwareX, doi:10.1016/j.softx.2015.06.001

Alexandris, Lagoumintzis, Chasapis, Leonidas, Papadopoulos et al., Nicotinic cholinergic system and COVID-19: in silico evaluation of nicotinic acetylcholine receptor agonists as potential therapeutic interventions, Toxicol. Reports, doi:10.1016/j.toxrep.2020.12.013

Arshad, Kilgore, Chaudhry, Jacobsen, Wang et al., Treatment with hydroxychloroquine, azithromycin, and combination in patients hospitalized with COVID-19, Int J Infect Dis, doi:10.1016/j.ijid.2020.06.099

Baildya, Ghosh, Chattopadhyay, Inhibitory capacity of chloroquine against SARS-COV-2 by effective binding with angiotensin converting enzyme-2 receptor: an insight from molecular docking and MD-simulation studies, J Mol Struct, doi:10.1016/j.molstruc.2021.129891

Ballestero, Plazas, Kracun, Gómez-Casati, Taranda et al., Effects of quinine, quinidine, and chloroquine on α9α10 nicotinic cholinergic receptors, Mol Pharmacol, doi:10.1124/mol.105.014431

Battle, PDBePISA : Identifying and interpreting the likely biological assemblies of a protein structure What is PDBePISA ? Where does the data come from ? PDBePISA for analysing the NGF structure 1bet Starting the PDBePISA service

Castrignanò, Meo, Cozzetto, Talamo, Tramontano, The PMDB protein model database, Nucleic Acids Res, doi:10.1093/nar/gkj105

Celı˙k, Onay-Besı˙kcı˙a, Kilcigı˙l, Approach to the mechanism of action of hydroxychloroquine on SARS-CoV-2: a molecular docking study, J Biomol Struct Dyn, doi:10.1080/07391102.2020.1792993

Chen, Chen, Dong, Huang, Chen et al., The effects of chloroquine and hydroxychloroquine on ACE2-related coronavirus pathology and the cardiovascular system: an evidence-based review, Function, doi:10.1093/function/zqaa012

Cohen, Yielding, Inhibition of DNA and RNA polymerase reactions by chloroquine, Proc Natl Acad Sci, doi:10.1073/pnas.54.2.521

Colovos, Yeates, Verification of protein structures: patterns of nonbonded atomic interactions, Protein Sci, doi:10.1002/pro.5560020916

Consortium, The universal protein resource (UniProt), Nucleic Acids Res, doi:10.1093/NAR/GKM895

Daina, Michielin, Zoete, SwissTargetPrediction: updated data and new features for efficient prediction of protein targets of small molecules, Nucleic Acids Res, doi:10.1093/nar/gkz382

Delano, Pymol: an open-source molecular graphics tool, CCP4 Newsl. Protein Crystallogr

Delbart, Brams, Gruss, Noppen, Peigneur et al., An allosteric binding site of the α7 nicotinic acetylcholine receptor revealed in a humanized acetylcholine-binding protein, J Biol Chem, doi:10.1074/jbc.M117.815316

Devaux, Rolain, Colson, Raoult, New insights on the antiviral effects of chloroquine against coronavirus: what to expect for COVID-19?, Int J Antimicrob Agents, doi:10.1016/j.ijantimicag.2020.105938

Dominguez, Boelens, Bonvin, HADDOCK. A protein-protein docking approach based on biochemical or biophysical information, J Am Chem Soc, doi:10.1021/ja026939x

Eichborn, Murgueitio, Dunkel, Koerner, Bourne et al., PROMISCUOUS: a database for network-based drug-repositioning, Nucleic Acids Res, doi:10.1093/nar/gkq1037

Eldanasory, Eljaaly, Memish, Tawfiq, Histamine release theory and roles of antihistamine in the treatment of cytokines storm of COVID-19, Travel Med. Inf Disp, doi:10.1016/j.tmaid.2020.101874

Emsley, Cowtan, Coot: model-building tools for molecular graphics, Acta Crystallogr Sect D Biol Crystallogr, doi:10.1107/S0907444904019158

Fragkou, Belhadi, Peiffer-Smadja, Moschopoulos, Lescure et al., Review of trials currently testing treatment and prevention of COVID-19, Clin Microbiol Infect, doi:10.1016/j.cmi.2020.05.019

Friesner, Banks, Murphy, Halgren, Klicic et al., Glide: a new approach for rapid, accurate docking and scoring. 1. Method and assessment of docking accuracy, J Med Chem, doi:10.1021/jm0306430

Gaulton, Bellis, Bento, Chambers, Davies et al., ChEMBL: a large-scale bioactivity database for drug discovery, Nucleic Acids Res, doi:10.1093/nar/gkr777

Gentile, Fuochi, Rescifina, Furneri, New anti sars-cov-2 targets for quinoline derivatives chloroquine and hydroxychloroquine †, Int J Mol Sci, doi:10.3390/ijms21165856

Gheblawi, Wang, Viveiros, Nguyen, Zhong et al., SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2, Angiotensin-converting enzyme, doi:10.1161/CIRCRESAHA.120.317015

Gm, Aa, Sf, Dj, Tl, Domain enhanced lookup time accelerated BLAST, Biol Direct, doi:10.1186/1745-6150-7-12

Goto-Ito, Yamagata, Takahashi, Sato, Fukai, Structural basis of the interaction between Topoisomerase IIIβ and the TDRD3 auxiliary factor, Sci Rep, doi:10.1038/srep42123

Guo, Ye, Pan, Chen, Xing et al., New insights of emerging SARS-CoV-2: epidemiology, etiology, clinical features, clinical treatment, and prevention, Front. Cell Dev. Biol, doi:10.3389/fcell.2020.00410

Halgren, New method for fast and accurate binding-site identification and analysis, Chem Biol Drug Des, doi:10.1111/j.1747-0285.2007.00483.x

Hecker, Ahmed, Eichborn, Dunkel, Macha et al., SuperTarget goes quantitative: update on drug-target interactions, Nucleic Acids Res, doi:10.1093/nar/gkr912

Ho, Mok, Campisi, Jordan, Yildiz et al., TOP1 inhibition therapy protects against SARS-CoV-2-induced lethal inflammation, Cell, doi:10.1016/j.cell.2021.03.051

Huang, Yang, Xu, Xu, Liu, Structural and functional properties of SARS-CoV-2 spike protein: potential antivirus drug development for COVID-19

Keiser, Roth, Armbruster, Ernsberger, Irwin et al., Relating protein pharmacology by ligand chemistry, Nat Biotechnol, doi:10.1038/nbt1284

Kim, Chivian, Baker, Protein structure prediction and analysis using the Robetta server, Nucleic Acids Res, doi:10.1093/nar/gkh468

Kono, Tatsumi, Imai, Saito, Kuriyama et al., Inhibition of human coronavirus 229E infection in human epithelial lung cells (L132) by chloroquine: involvement of p38 MAPK and ERK, Antivir Res, doi:10.1016/j.antiviral.2007.10.011

Kozakov, Hall, Xia, Porter, Padhorny et al., The ClusPro web server for protein-protein docking, Nat Protoc, doi:10.1038/nprot.2016.169

Kumari, Kumar, G-mmpbsa -A GROMACS tool for high-throughput MM-PBSA calculations, J Chem Inf Model, doi:10.1021/ci500020m

Lagoumintzis, Chasapis, Alexandris, Kouretas, Tzartos et al., Nicotinic cholinergic system and COVID-19: in silico identification of interactions between α7 nicotinic acetylcholine receptor and the cryptic epitopes of SARS-Co-V and SARS-CoV-2 Spike glycoproteins, Food Chem Toxicol, doi:10.1016/j.fct.2021.112009

Laskowski, Macarthur, Moss, Thornton, PROCHECK: a program to check the stereochemical quality of protein structures, J Appl Crystallogr, doi:10.1107/S0021889892009944

Laskowski, Swindells, LigPlot+: multiple ligand-protein interaction diagrams for drug discovery, J Chem Inf Model, doi:10.1021/CI200227U

Liu, Cao, Xu, Wang, Zhang et al., Hydroxychloroquine, a less toxic derivative of chloroquine, is effective in inhibiting SARS-CoV-2 infection in vitro, Cell Discov, doi:10.1038/s41421-020-0156-0

Malde, Zuo, Breeze, Stroet, Poger et al., An automated force field topology builder (ATB) and repository: version 1.0, J Chem Theor Comput, doi:10.1021/ct200196m

Masureel, Zou, Picard, Van Der Westhuizen, Mahoney et al., Structural insights into binding specificity, efficacy and bias of a β 2 AR partial agonist, Nat Chem Biol, doi:10.1038/s41589-018-0145-x

Matrosovich, Herrler, Klenk, Sialic acid receptors of viruses, Top Curr Chem, doi:10.1007/128_2013_466

Mj, Brickner, Hamel, Brennan, Casavant et al., Novel quinoline derivatives as inhibitors of bacterial DNA gyrase and topoisomerase IV, Bioorg Med Chem Lett, doi:10.1016/j.bmcl.2013.03.047

Nakazawa, Sekizawa, Morikawa, Yamauchi, Satoh et al., Viral respiratory infection causes airway hyperresponsiveness and decreases histamine N-methyltransferase activity in Guinea pigs, Am J Respir Crit Care Med, doi:10.1164/ajrccm.149.5.8173757

Nirthanan, Gwee, Three-finger α-neurotoxins and the nicotinic acetylcholine receptor, forty Years on, J Pharmacol Sci, doi:10.1254/jphs.94.1

Oliveira, Ibarra, Bermudez, Casalino, Gaieb et al., Simulations support the interaction of the SARS-CoV-2 spike protein with nicotinic acetylcholine receptors, BioRxiv Prepr. Serv. Biol, doi:10.1101/2020.07.16.206680

Prasanth, Hirano, Fagg, Mcanarney, Shan et al., Topoisomerase III-ß is required for efficient replication of positive-sense RNA viruses, BioRxiv, doi:10.1101/2020.03.24.005900

Prodromos, Rumschlag, Hydroxychloroquine is effective, and consistently so when provided early, for COVID-19: a systematic review, New Microbes New Infect, doi:10.1016/j.nmni.2020.100776

Roldan, Biasiotto, Magro, Zanella, The possible mechanisms of action of 4-aminoquinolines (chloroquine/hydroxychloroquine) against Sars-Cov-2 infection (COVID-19): a role for iron homeostasis?, Pharmacol Res, doi:10.1016/j.phrs.2020.104904

Rose, Graham, Koenecke, Powell, Xiong et al., The association between alpha-1 adrenergic receptor antagonists and in-hospital mortality from COVID-19, Front Med, doi:10.3389/fmed.2021.637647

Sastry, Adzhigirey, Day, Annabhimoju, Sherman, Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments, J Comput Aided Mol Des, doi:10.1007/s10822-013-9644-8

Schrezenmeier, Dörner, Mechanisms of action of hydroxychloroquine and chloroquine: implications for rheumatology, Nat Rev Rheumatol, doi:10.1038/s41584-020-0372-x

Sine, Engel, Recent advances in Cys-loop receptor structure and function, Nature, doi:10.1038/nature04708

Singh, Chauhan, Kakkar, Hydroxychloroquine for the treatment and prophylaxis of COVID-19: the journey so far and the road ahead, Eur J Pharmacol, doi:10.1016/j.ejphar.2020.173717

Singh, Singh, Shaikh, Singh, Misra, Chloroquine and hydroxychloroquine in the treatment of COVID-19 with or without diabetes: a systematic search and a narrative review with a special reference to India and other developing countries, Diabetes Metab. Syndr. Clin. Res. Rev, doi:10.1016/j.dsx.2020.03.011

Skariyachan, Gopal, Chakrabarti, Kempanna, Uttarkar et al., Structural and molecular basis of the interaction mechanism of selected drugs towards multiple targets of SARS-CoV-2 by molecular docking and dynamic simulation studies-deciphering the scope of repurposed drugs, Comput Biol Med, doi:10.1016/j.compbiomed.2020.104054

Steinbach, Mechanism of action of the nicotinic acetylcholine receptor, Ciba Found Symp, doi:10.1002/9780470513965.ch4

Tang, Liu, Zhang, Xu, Wen, Cytokine storm in COVID-19: the current evidence and treatment strategies, Front Immunol, doi:10.3389/fimmu.2020.01708

Towler, Staker, Prasad, Menon, Tang et al., ACE2 X-ray structures reveal a large hinge-bending motion important for inhibitor binding and catalysis, J Biol Chem, doi:10.1074/jbc.M311191200

Trott, Olson, Autodock vina: improving the speed and accuracy of docking, J Comput Chem, doi:10.1002/jcc.21334.AutoDock

Wang, Cao, Zhang, Yang, Liu et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro, Cell Res, doi:10.1038/s41422-020-0282-0

Wang, Thomae, Eckloff, Wieben, Weinshilboum, Human histamine Nmethyltransferase pharmacogenetics: gene resequencing, promoter characterization, and functional studies of a common 5 ′ -flanking region single nucleotide polymorphism (SNP), Biochem Pharmacol, doi:10.1016/S0006-2952(02)01223-6

Wang, Zhang, Wu, Niu, Song et al., Structural and functional basis of SARS-CoV-2 entry by using human ACE2, Cell, doi:10.1016/j.cell.2020.03.045

Wiederstein, Sippl, ProSA-web: interactive web service for the recognition of errors in three-dimensional structures of proteins, Nucleic Acids Res, doi:10.1093/NAR/GKM290

Willard, Ranjan, Zhang, Monzavi, Boyko et al., VADAR: a web server for quantitative evaluation of protein structure quality, Nucleic Acids Res, doi:10.1093/NAR/GKG565

Wishart, Feunang, Guo, Lo, Marcu et al., DrugBank 5.0: a major update to the DrugBank database for 2018, Nucleic Acids Res, doi:10.1093/nar/gkx1037

Download Image

Please send us corrections, updates, or comments. c19early involves the extraction of 100,000+ datapoints from thousands of papers. Community updates help ensure high accuracy. Treatments and other interventions are complementary. All practical, effective, and safe means should be used based on risk/benefit analysis. No treatment or intervention is 100% available and effective for all current and future variants. We do not provide medical advice. Before taking any medication, consult a qualified physician who can provide personalized advice and details of risks and benefits based on your medical history and situation. FLCCC and WCH provide treatment protocols.

Submit

Post

@CovidAnalysis

FAQ

Public domain CC0 1.0