La acelerada búsqueda de candidatos terapéuticos contra SARS-CoV-2, métodos in silico: Revisión

Oscar Cobar, Rodrigo J. Vargas


El reposicionamiento de fármacos como la derivatización química, que se han aplicado en los estudios de descubrimiento y diseño de fármacos contra el SARS-CoV-2, dependen del ciclo de vida del virus, las dianas moleculares identificadas y un diseño basado en su estructura e interacciones moleculares. Se realizó una revisión extensa en las bases de datos públicas e institucionales RSCB-Protein Data Bank, ZINC, NCBI (PubMed, PMC), PubChem, Science Direct e instituciones como CDC, NIH y revistas científicas especializadas sobre los avances en la búsqueda de nuevas moléculas contra el nuevo coronavirus basadas en estudios in silico, detectándose más de 40,000 publicaciones sobre SARS-CoV-2 y cerca de 200 relacionadas a dichos estudios, las consideradas más relevantes fueron analizadas e incluidas en este artículo. Su análisis evidencia el avance acelerado de las herramientas computacionales y fortaleza del diseño de fármacos asistido por computadora (in silico approach) para la generación de nuevas moléculas con posibilidad de ser activas contra COVID-19 y presenta las principales dianas moleculares sobre la que actúan estos agentes con potencial antiviral.

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Adam, S., Eyupoglu, V., Sarfraz, I., Rasuli, A., & Ali, M (2020). Identification of potent Covid-19 main protease (Mpro) inhibitors from natural polyphenols: An in silico strategy unveils a hope against Corona. Preprints.

Bhardwaj, R. (2020). A predictive model for the evolution of COVID-19. Transactions of the Indian National Academy of Engineering, 5, 133-140.

Bianchi, M., Benvenuto, D., Giovanetti, M., Angeletti, S., Ciccozzi, M., & Pascarella, S. (2020). SARS-CoV-2 envelope and membrane proteins: Differences from closely related proteins linked to cross-species transmission? BioMed Research International. Article 4389089.

Boopathi, S., Poma, A. B., & Kolandaivel, P. (2020). Novel 2019 coronavirus structure, mechanism of action, antiviral drug promises and rule out against its treatment. Journal of Biomolecular Structure and Dynamics.

Bosch, B. J., van der Zee, R., de Haan, C. A. M., & Rottier, P. J. M. (2003). The Coronavirus spike protein is a class I virus fusion protein: Structural and functional characterization of the fusion core complex. Journal of Virology, 77(16), 8801-8811.

Bruno, A., Costantino, G., Sartori, L., & Radi, M. (2019). The in silico drug discovery toolbox: Applications in lead discovery and optimization. Current Medicinal Chemistry, 26(21), 3838-3873.

Bzówka, M., Mitusi?ska, K., Raczy?ska, A., Samol, A., Tuszy?ski, J., & Góra, A. (2020). Structural and evolutionary analysis indicate that the SARS-CoV-2 Mpro is a challenging target for small-molecule inhibitor design. International Journal of Molecular Science, 21(9), Article 3099.

Cava, C., Bertoli, G., & Castiglioni, I. (2020). In silico discovery of candidate drugs against Covid-19. Viruses, 12(4), Article 404.

Chaccour, C., Hamman, F., Ramón-García, S., & Rabinovich, R. (2020). Ivermectin and COVID-19: Keeping rigor in times of urgency. The American Journal of Tropical Medicine and Hygiene, 102(6), 1156-1157.

Chamdel, V., Raj, S., Rathi, B. & Kumar, D. (2020). In silico identification of potent Covid-19 main protease inhibitors from FDA approved antiviral compounds and active phytochemicals through molecular docking: A drug repurposing approach. Preprints.

Chen, C., Zhang, Y., Huang, J., Yin, P., Cheng, Z., Wu, J., … Wang, X. (2020). Favipiravir versus arbidol for COVID-19: A randomized clinical trial. MedRxiv.

Choudhury, A., & Mukherjee, S. (2020). In silico studies on the comparative characterization of the interactions of SARS?CoV?2 spike glycoprotein with ACE?2 receptor homologs and human TLRs. Journal of Medical Virology, 92(10).

Corrêa, C., Laaksonen, A., & Barroso da Silva, F. L. (2020). On the interactions of the receptor-binding domain of SARS-CoV-1 and SARS-CoV-2 spike proteins with monoclonal antibodies and the receptor ACE2. Virus Research, 285, Article 198021.

Durdagi, S. (2020). Virtual drug repurposing study against SARS-CoV-2 TMPRSS2 target. Turkish Journal of Biology, 44(3), 185-191.

Durojaiye, A. B., Clarke, J.-R. D., Stamatiades, G. A., & Wang, C. (2020). Repurposing cefuroxime for treatment of COVID-19: A scoping review of in silico studies. Journal of Biomolecular Structure & Dynamics.

Eaaswarkhanth, M., Al Madhoun, A., & Al-Mulla, F. (2020). Could the D614G substitution in the SARS-CoV-2 spike (S) protein be associated with higher COVID-19 mortality? International Journal of Infectious Diseases, 96, 459-460.

Elmezayen, A. D., Al-Obaidi, A., ?ahin, A. T., & Yelekçi, K. (2020). Drug repurposing for coronavirus (COVID-19): In silico screening of known drugs against coronavirus 3CL hydrolase and protease enzymes. Journal of Biomolecular Structure & Dynamics.

Estrada, E. (2020). Topological analysis of SARS CoV-2 main protease. Chaos: An Interdisciplinary Journal of Nonlinear Science, 30(6), 061102.

Erlina, L., Paramita, R. I., Kusuma, W. A., Fadilah, F., Tedjo, A., Pratomo, I. P., ... Yanur, A. (2020). Virtual screening on Indonesian herbal compounds as COVID-19 supportive therapy: Machine learning and pharmacophore modeling approaches. Research Square.

Farag, A. B., Wang, P., Ahmed, M. S., & Sadek, H. A. (2020). Identification of FDA approved drugs targeting COVID-19 virus by structure-based drug repositioning. ChemRxiv.

Ganesan, A., Arimondo, P. B., Rots, M. G., Jeronimo, C., & Berdasco, M. (2019). The timeline of epigenetic drug discovery: From reality to dreams. Clinical Epigenetics, 11(1), 174.

Gao, Y., Yan, L., Huang, Y., Liu, F., Zhao, Y., Cao, L., ... Ge, J. (2020). Structure of RNA-dependent RNA polymerase from COVID-19 virus. Science, 368(6492), 779-782.

Gentile, F., Agrawal, V., Hsing, M., Ton, A.-T., Ban, F., Norinder, U., … Cherkasov, A. (2020). Deep docking: A deep learning platform for augmentation of structure based drug discovery. ACS Central Science, 6(6), 939-949.

Ghosh, R., Chakraborty, A., Biswas, A., & Chowdhuri, S. (2020). Evaluation of green tea polyphenols as novel corona virus (SARS CoV-2) main protease (Mpro) inhibitors – an in silico docking and molecular dynamics simulation study. Journal of Biomolecular Structure & Dynamics, 1-13.

Glowacka, I., Bertram, S., Müller, M. A., Allen, P., Soilleux, E., Pfefferle, S., … Pöhlmann, S. (2011). Evidence that TMPRSS2 activates the severe acute respiratory syndrome coronavirus spike protein for membrane fusion and reduces viral control by the humoral immune response. Journal of Virology, 85(9), 4122-4134.

Gonzalez-Paz, L. A., Lossada, C. A., Moncayo, L. S., Romero, F., Paz, J. L., Vera-Villalobos, J. … Alvarado, Y. J. (2020). Theoretical molecular docking study of the structural disruption of the viral 3CL-protease of COVID19 induced by binding of capsaicin, piperine and curcumin Part 1: A comparative study with chloroquine and hydrochloroquine to antimalaric drugs. Research Square, preprint.

Hall, D. C., & Ji, H.-F. (2020). A search for medications to treat COVID-19 via in silico molecular docking models of the SARS-CoV-2 spike glycoprotein and 3CL protease. Travel Medicine and Infectious Disease, 35, 101646.

Hashem, H. E. (2020). In Silico approach of some selected honey constituents as SARS-CoV-2 main protease (COVID-19) inhibitors. ChemRxiv.

Hoffmann, M., Hofmann-Winkler, H., & Pöhlmann, S. (2018). Priming time: How cellular proteases arm coronavirus spike proteins. En E. Böttcher-Friebertshäuser, W. Garten & H. D. Klenk (Eds.), Activation of Viruses by Host Proteases (pp. 71-98). Cham: Springer.

Hoffmann, M., Kleine-Weber, H., Krüger, N., Müller, M., Drosten, C., & Pöhlmann, S. (2020). The novel coronavirus 2019 (2019-nCoV) uses the SARS-coronavirus receptor ACE2 and the cellular protease TMPRSS2 for entry into target cells. BioRxiv.

Holshue, M. L., DeBolt, C., Lindquist, S., Lofy, K. H., Wiesman, J., Bruce, H., … Pillai, S. K. (2020). First case of 2019 novel coronavirus in the United States. New England Journal of Medicine, 382(10), 929-936.

Huang, Y., Yang, C., Xu, X.-F., Xu, W., & Liu, S.-w. (2020). Structural and functional properties of SARS-CoV-2 spike protein: Potential antivirus drug development for COVID-19. Acta Pharmacologica Sinica, 41, 1141-1149.

Hung, H.-C., Ke, Y.-Y., Huang, S. Y., Huang, P.-N., Kung, Y.-A., Chang, T.-Y., … Hsu, J. T.-A. (2020). Discovery of M protease inhibitors encoded by SARS-CoV-2. Antimicrobial Agents and Chemotherapy, 64, Article e200872.

Huynh, T., Wang, H., & Luan, B. (2020). In silico exploration of the molecular mechanism of clinically oriented drugs for possibly inhibiting SARS-CoV-2’s main protease. Journal of Physical Chemistry Letters, 11(11), 4413-4420.

Jiménez-Alberto, A., Ribas-Aparicio, R. M., Aparicio-Ozores, G., & Castelán-Vega, J. A. (2020). Virtual screening of approved drugs as potential SARS-CoV-2 main protease inhibitors. Computational Biology and Chemistry, 88, 107325.

Jin, Z., Du, X., Xu, Y., Deng, Y., Liu, M., Zhao, Y., … Yang, H. (2020). Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature, 582(7811), 289-293.

Jokhakar, P. H., Kalaria, R., & Patel, H. K. (2020). In silico docking studies of antimalarial drug hydroxychloroquine to SARS-CoV proteins: An emerging pandemic worldwide. ChemRxiv.

Joshi, T., Joshi, T., Sharma, P., Mathpal, S., Pundir, H., Bhatt, V., & Chandra, S. (2020). In silico screening of natural compounds against COVID-19 by targeting Mpro and ACE2 using molecular docking. European Review for Medical and Pharmacological Sciences, 24(8), 4529-4536.

Joshi, T., Sharma, P., Joshi, T., Pundir, H., Mathpal, S., & Chandra, S. (2020). Structure-based screening of novel lichen compounds against SARS Coronavirus main protease (Mpro) as potentials inhibitors of COVID-19. Molecular Diversity.

Kadioglu, O., Saeed, M., Greten, H. J., & Efferth, T. (2020). Identification of novel compounds against three targets of SARS CoV-2 coronavirus by combined virtual screening and supervised machine learning. [Preprint]. Bulletin of the World Health Organization.

Kaitin, K. I. (2010). Deconstructing the drug development process: The new face of innovation. Clinical Pharmacology & Therapeutics, 87(3), 356-361.

Kandeel, M., & Al-Nazawi, M. (2020). Virtual screening and repurposing of FDA approved drugs against COVID-19 main protease. Life Sciences, 251, 117627.

Kapetanovic, I. M. (2008). Computer-aided drug discovery and development (CADDD): In silico-chemico-biological approach. Chemico-Biological Interactions, 171(2), 165-176.

Khaerunnisa, S., Kurniawa, H., Avaluddin, R., Suhartati, S., & Soetjipto, S. (2020). Potential inhibitor of Covid-19 main protease (Mpro) from several medicinal plant compounds by molecular docking study. Preprints.

Kim, D., Lee, J.-Y., Yang, J.-S-, Kim, J.-W., Kim, V. N., & Chang, H. (2020). The architecture of SARS-CoV-2 transcriptome. Cell, 181(4), 914-921.e10.

Korber, B., Fischer, W., Gnanakaran, S., Yoon, H., Theiler, J., Abfalterer, W., … Montefiori, D. (2020). Tracking changes in SARS-CoV-2 spike: Evidence that D614G increases infectivity of the COVID-19 virus. Cell, 182(4), 812-827.e19.

Kumar, D., Chandel, V., Raj, S., & Rathi, B. (2020). In silico identification of potent FDA approved drugs against Coronavirus COVID-19 main protease: A drug repurposing approach. Chemical Biology Letters, 7(3), 166-175.

Kumar, Y., Singh, H., & Patel, C. N. (2020). In silico prediction of potential inhibitors for the main protease of SARS-CoV-2 using molecular docking and dynamics simulation based drug-repurposing. Journal of Infection and Public Health, 13(9), 1210-1223.

Lagunin, A. A., Goel, R. K., Gawande, D. Y., Pahwa, P., Gloriozova, T. A., Dmitriev, A. V., … Poroikov, V. V. (2014). Chemo- and bioinformatics resources for in silico drug discovery from medicinal plants beyond their traditional use: A critical review. Natural Product Reports, 31(11), 1585-1611.

Leelananda, S. P., & Lindert, S. (2016). Computational methods in drug discovery. Beilstein Journal of Organic Chemistry, 12(1), 2694-2718.

Li, F., Li, W., Farzan, M., & Harrison, S. C. (2005). Structure of SARS coronavirus spike receptor-binding domain complexed with receptor. Science, 309(5742), 1864-1868.

Li, G., & De Clercq, E. (2020). Therapeutic options for the 2019 novel coronavirus (2019-nCoV). Nature Reviews Drug Discovery, 19(3), 149-150.

Li, H., Zhou, Y., Zhang, M., Wang, H., Zhao, Q., & Liu, J. (2020). Updated approaches against SARS-CoV-2. Antimicrobial Agents and Chemotherapy, 64(6), Article e00483-20.

Li, W., Moore, M. J., Vasilieva, N., Sui, J., Wong, S. K., Berne, M. A., … Farzan, M. (2003). Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature, 426(6965), 450-454.

Li, W., Zhang, C., Sui, J., Kuhn, J. H., Moore, M. J., Luo, S., … Farzan, M. (2005). Receptor and viral determinants of SARS?coronavirus adaptation to human ACE2. The EMBO Journal, 24(8), 1634-1643.

Liu, C., Zhou, Q., Li, Y., Garner, L. V., Watkins, S. P., Carter, L. J., … Albaiu, D. (2020). Research and development on therapeutic agents and vaccines for COVID-19 and related human Coronavirus diseases. ACS Central Science, 6(3), 315-331.

Lukassen, S., Chua, R. L., Trefzer, T., Kahn, N. C., Schneider, M. A., Muley, T., … Eils, R. (2020). SARS-CoV-2 receptor ACE2 and TMPRSS2 are predominantly expressed in a transient secretory cell type in subsegmental bronchial branches. BioRxiv.

Mahanta, S., Chowdhury, P., Gogoi, N., Goswami, N., Borah, D., Kumar, R., … Gogoi, B. (2020). Potential anti-viral activity of approved repurposed drug against main protease of SARS-CoV-2: An in silico based approach. Journal of Biomolecular Structure and Dynamics, 1-10.

Maranon, D. G., Anderson, J. R., Maranon, A. G., & Wilusz, J. (2020). The interface between coronaviruses and host cell RNA biology: Novel potential insights for future therapeutic intervention. Wiley Interdisciplinary Reviews. RNA, 11(5), Article e1614.

Matsuyama, S., Nagata, N., Shirato, K., Kawase, M., Takeda, M., & Taguchi, F. (2010). Efficient activation of the severe acute respiratory syndrome coronavirus spike protein by the transmembrane protease TMPRSS2. Journal of Virology, 84(24), 12658-12664.

Meyer, D., Sielaff, F., Hammami, M., Bottcher-Friebertshauser, E., Garten, W., & Steinmetzer, T. (2013). Identification of the first synthetic inhibitors of the type II transmembrane serine protease TMPRSS2 suitable for inhibition of influenza virus activation. Biochemical Journal, 452(2), 331-343.

Mirza, M. U., & Froeyen, M. (2020). Structural elucidation of SARS-CoV-2 vital proteins: Computational methods reveal potential drug candidates against main protease, Nsp12 polymerase and Nsp13 helicase. Journal of Pharmaceutical Analysis, 10(4), 320-328.

Mishra, A., Pathak, Y., Choudhir, G., Kumar, A., Mishra, S. K., & Tripathi, V. (2020). Natural compounds as potential inhibitors of novel coronavirus (COVID-19) main protease: An in silico study. Research Square, preprint.

Monaghan, R. L., & Barrett, J. F. (2006). Antibacterial drug discovery - Then, now and the genomics future. Biochemical Pharmacology, 71(7), 901-909.

Naik, V. R., Munikumar, M., Ramakrishna, U., Srujana, M., Goudar, G., Naresh, P., ... Hemalatha, R. (2020). Remdesivir (GS-5734) as a therapeutic option of 2019-nCOV main protease – in silico approach. Journal of Biomolecular Structure & Dynamics, 1-14.

Narkhede, R. R., Pise, A. V., Cheke, R. S., & Shinde, S. D. (2020). Recognition of natural products as potential inhibitors of COVID-19 main protease (Mpro): In-silico evidences. Natural Products and Bioprospecting, 10, 297-306.

Oliveira, A. S. F., Ibarra, A. A., Bermudez, I., Casalino, L., Gaieb, Z., Shoemark, D. K., … Mulholland, A. J. (2020). Simulations support the interaction of the SARS-CoV-2 spike protein with nicotinic acetylcholine receptors and suggest subtype specificity. BioRxiv.

Pachetti, M., Marini, B., Benedetti, F., Giudici, F., Mauro, E., Storici, P., … Ippodrino, R. (2020). Emerging SARS-CoV-2 mutation hot spots include a novel RNA-dependent-RNA polymerase variant. Journal of Translational Medicine 18, Article 179.

Paz, L. A. G., Lossada, C. A., Moncayo, L. S., Romero, F., Paz, J. L., Vera-Villalobos, … Alvarado, Y. J. (2020). Molecular docking and molecular dynamic study of two viral proteins associated with SARS-CoV-2 with ivermectin. Preprints.

Peterson, L. E. (2020). COVID-19 and flavonoids: In silico molecular dynamics docking to the active catalytic site of SARS-CoV and SARS-CoV-2 main protease. Social Science Research Network.

Rahman, N., Basharat, Z., Yousuf, M., Castaldo G., Rastrelli, L., & Khan, H. (2020). Virtual screening of natural products against type II transmembrane serine protease (TMPRSS2), the priming agent of Coronavirus 2 (SARS-CoV-2). Molecules, 25(10), 2271.

Rensi, S., Altman, R. B., Liu, T., Lo, Y.-C., McInnes, G., Derry, A., & Keys, A. (2020). Homology modeling of TMPRSS2 yields candidate drugs that may inhibit entry of SARS-CoV-2 into human cells. ChemRxiv.

Rut, W., Groborz, K., Zhang, L., Sun, X., Zmudzinski, M., Pawlik, B., … Drag, M. (2020). Substrate specificity profiling of SARS-CoV-2 main protease enables design of activity-based probes for patient-sample imaging. BioRxiv.

Sanders, J. M., Monogue, M. L., Jodlowski, T. Z., & Cutrell, J. B. (2020). Pharmacologic treatments for coronavirus disease 2019 (COVID-19): A review. Journal of the American Medical Association, 323(18), 1824-1836.

Shah, B., Modi, P., & Sagar, S. R. (2020). In silico studies on therapeutic agents for COVID-19: Drug repurposing approach. Life Sciences, 252, 117652.

Shamsi, A., Mohammad, T., Anwar, S., Al Ajmi, M. F., Hussain, A., Rehman, M. T., … Hassan, M. I. (2020). Glecaprevir and Maraviroc are high-affinity inhibitors of SARS-CoV-2 main protease: Possible implication in COVID-19 therapy. Bioscience Reports, 40(6), BSR20201256.

Shrimp, J. H., Kales, S. C., Sanderson, P. E., Simeonov, A., Shen, M., & Hall, M. D. (2020). An enzymatic TMPRSS2 assay for assessment of clinical candidates and discovery of inhibitors as potential treatment of COVID-19. BioRxiv.

Shulla, A., Heald-Sargent, T., Subramanya, G., Zhao, J., Perlman, S., & Gallagher, T. (2011). A transmembrane serine protease is linked to the severe acute respiratory syndrome Coronavirus receptor and activates virus entry. Journal of Virology, 85(2), 873-882.

Sisay, M. (2020). Available evidence and ongoing clinical trials of remdesivir: Could it be a promising therapeutic option for COVID-19? Frontiers in Pharmacology, 11, 791.

Srinivasan, S., Cui, H., Gao, Z., Liu, M., Lu, S., Mkandawire, W., ... Korkin, D. (2020). Structural genomics of SARS-CoV-2 indicates evolutionary conserved functional regions of viral proteins. Viruses, 12(4), 360.

Srivastava, A. K., Kumar, A., Tiwari, G., Kumar, R., & Misra, N. (2020). In silico investigations on the potential inhibitors for COVID-19 protease. ArXiv. arXiv:2003.10642v2

Tan, Q., & Jin, Y. (2020). Oseltavimir is ineffective against COVID-19: In silico assessment, in vitro and retrospective study. MedRxiv.

Terstappen, G. C., & Reggiani, A. (2001). In silico research in drug discovery. Trends in Pharmacological Sciences, 22(1), 23-26.

Ton, A.-T., Gentile, F., Hsing, M., Ban, F., & Cherkasov, A. (2020). Rapid identification of potential inhibitors of SARS?CoV?2 main protease by deep docking of 1.3 billion compounds. Molecular Informatics, 39(8).

Ullrich, S., & Nitsche, C. (2020). The SARS-CoV-2 main protease as drug target. Bioorganic & Medicinal Chemistry Letters, 30(17), 127377.

Umesh, Kundu, D., Selvaraj, C., Singh, S. K., & Dubey, V. K. (2020). Identification of new anti-nCoV drug chemical compounds from Indian spices exploiting SARS-CoV-2 main protease as target. Journal of Biomolecular Structure & Dynamics.

Wang, Y., Zhang, D., Guangua, G., Du, R., Zhao, J., Jin, Y., …Wang, C. (2020). Remdesivir in adults with severe COVID-19: A randomised, double-blind, placebo-controlled, multicentre trial. Lancet, 395(10236), 1569-1578.

Weinmann, H., & Metternich, R. (2005). Editorial: Drug discovery process for kinease inhibitors. ChemBioChem, 6(3), 455-459.

Wrapp, D., Wang, N., Corbett, K. S., Goldsmith, J. A., Hsieh, C.-L., Abiona, O., … McLellan, J. S. (2020). Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation. Science, 367(6483), 1260-1263.

Yoshino, R., Yasuo, N., & Sekijima, M. (2020). Identification of key interactions between SARS-CoV-2 main protease and inhibitor drug candidates. Scientific Reports, 10, 12493.

Zhang, L., Lin, D., Sun, X., Curth, U., Drosten, C., Sauerhering, L., … Hilgenfeld, R. (2020). Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved ?-ketoamide inhibitors. Science, 368(6489), 409-412.

Zhou, Y., Hou, Y., Shen, J., Huang, Y., Martin, W., & Cheng, F. (2020). Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discovery, 6(1), 1-18.


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