Current Computer-Aided Drug DesignCurrent Computer-Aided Drug DesignCurrent Computer-Aided Drug Design1573-40991875-6697Bentham Science64401310.2174/1573409919666230329090403ChemistryResearch ArticleComputer-aided Drug Discovery Approaches in the Identification of Natural Products against SARS-CoV-2: A ReviewJunqueira RibeiroMarianainfo@benthamscience.netFaculty of Pharmacy,, Estácio de Sá University0104202420431332407012025Copyright ©; 2024, Bentham Science Publishers2024Bentham Science Publishershttps://rjeid.com/1573-4099/article/view/644013

The COVID-19 pandemic is raising a worldwide search for compounds that could act against the disease, mainly due to its mortality. With this objective, many researchers invested in the discovery and development of drugs of natural origin. To assist in this search, the potential of computational tools to reduce the time and cost of the entire process is known. Thus, this review aimed to identify how these tools have helped in the identification of natural products against SARS-CoV-2. For this purpose, a literature review was carried out with scientific articles with this proposal where it was possible to observe that different classes of primary and, mainly, secondary metabolites were evaluated against different molecular targets, mostly being enzymes and spike, using computational techniques, with emphasis on the use of molecular docking. However, it is noted that in silico evaluations still have much to contribute to the identification of an anti- SARS-CoV-2 substance, due to the vast chemical diversity of natural products, identification and use of different molecular targets and computational advancement.

Computational studiesCOVID-19&lti&ampgtin silico&amplt/i&ampgtapproachmolecular dynamicmolecular modelingprimary and secondary metabolites.Wambani, J.; Okoth, P. SARS-CoV-2 origin, myths and diagnostic technology developments. Egypt. J. Med. Hum. Genet., 2022, 23(1), 42. doi: 10.1186/s43042-022-00255-3Yan, W.; Zheng, Y.; Zeng, X.; He, B.; Cheng, W. Structural biology of SARS-CoV-2: Open the door for novel therapies. Signal Transduct. Target. Ther., 2022, 7(1), 26. doi: 10.1038/s41392-022-00884-5 PMID: 35087058Lundstrom, K. Hromić-Jahjefendić A.; Bilajac, E.; Aljabali, A.A.A.; Baralić K.; Sabri, N.A.; Shehata, E.M.; Raslan, M.; Ferreira, A.C.B.H.; Orlandi, L.; Serrano-Aroca, Á.; Tambuwala, M.M.; Uversky, V.N.; Azevedo, V.; Alzahrani, K.J.; Alsharif, K.F.; Halawani, I.F.; Alzahrani, F.M.; Redwan, E.M.; Barh, D. COVID-19 signalome: Pathways for SARS-CoV-2 infection and impact on COVID-19 associated comorbidity. Cell. Signal., 2023, 101, 110495. doi: 10.1016/j.cellsig.2022.110495 PMID: 36252792Mina, S.; Yaakoub, H.; Annweiler, C.; Dubée, V.; Papon, N. COVID-19 and Fungal infections: A double debacle. Microbes Infect., 2022, 24(8), 105039. doi: 10.1016/j.micinf.2022.105039 PMID: 36030024Aware, C.B.; Patil, D.N.; Suryawanshi, S.S.; Mali, P.R.; Rane, M.R.; Gurav, R.G.; Jadhav, J.P. Natural bioactive products as promising therapeutics: A review of natural product-based drug development. S. Afr. J. Bot., 2022, 151, 512-528. doi: 10.1016/j.sajb.2022.05.028Chen, W.; Wang, Z.; Wang, Y.; Li, Y. Natural bioactive molecules as potential agents against SARS-CoV-2. Front. Pharmacol., 2019, 12, 702472.Islam, F.; Bibi, S.; Meem, A.F.K.; Islam, M.M.; Rahaman, M.S.; Bepary, S.; Rahman, M.M.; Rahman, M.M.; Elzaki, A.; Kajoak, S.; Osman, H.; ElSamani, M.; Khandaker, M.U.; Idris, A.M.; Emran, T.B. Natural bioactive molecules: An alternative approach to the treatment and control of COVID-19. Int. J. Mol. Sci., 2021, 22(23), 12638. doi: 10.3390/ijms222312638 PMID: 34884440Singh, Y.D.; Jena, B.; Ningthoujam, R.; Panda, S.; Priyadarsini, P.; Pattanayak, S.; Panda, M.K.; Singh, M.C.; Satapathy, K.B. Potential bioactive molecules from natural products to combat against coronavirus. Adv. Trad. Med., 2022, 22(2), 259-270. doi: 10.1007/s13596-020-00496-wChandramouli, V.; Niraj, S.K.; Nair, K.G.; Joseph, J.; Aruni, W. Phytomolecules repurposed as COVID-19 inhibitors: Opportunity and challenges. Curr. Microbiol., 2021, 78(10), 3620-3633. doi: 10.1007/s00284-021-02639-x PMID: 34448061Chaves, O.A.; Fintelman-Rodrigues, N.; Wang, X.; Sacramento, C.Q.; Temerozo, J.R.; Ferreira, A.C.; Mattos, M.; Pereira-Dutra, F.; Bozza, P.T.; Castro-Faria-Neto, H.C.; Russo, J.J.; Ju, J.; Souza, T.M.L. Commercially available flavonols are better SARS-CoV-2 inhibitors than isoflavone and flavones. Viruses, 2022, 14(7), 1458. doi: 10.3390/v14071458 PMID: 35891437Dejani, N.N.; Elshabrawy, H.A.; Bezerra Filho, C.S.M.; de Sousa, D.P. Anticoronavirus and immunomodulatory phenolic compounds: Opportunities and pharmacotherapeutic perspectives. Biomolecules, 2021, 11(8), 1254. doi: 10.3390/biom11081254 PMID: 34439920Prajapati, S.K.; Malaiya, A.; Mishra, G.; Jain, D.; Kesharwani, P.; Mody, N.; Ahmadi, A.; Paliwal, R.; Jain, A. An exhaustive comprehension of the role of herbal medicines in Pre and Post-COVID manifestations. J. Ethnopharmacol., 2022, 296, 115420. doi: 10.1016/j.jep.2022.115420 PMID: 35654349Diniz, L.R.L.; Elshabrawy, H.A.; Souza, M.T.S.; Duarte, A.B.S.; Madhav, N.; de Sousa, D.P. Renoprotective effects of luteolin: Therapeutic potential for COVID-19-associated acute kidney injuries. Biomolecules, 2022, 12(11), 1544. doi: 10.3390/biom12111544 PMID: 36358895Yusuf, A.P. Herbal medications and natural products for patients with COVID-19 and diabetes mellitus: Potentials and challenges. Phytomed. Plus, 2022, 2(3), 100280.Shaker, B.; Ahmad, S.; Lee, J.; Jung, C.; Na, D. In silico methods and tools for drug discovery. Comput. Biol. Med., 2021, 137, 104851. doi: 10.1016/j.compbiomed.2021.104851 PMID: 34520990Chikhale, H.; Rishipathak, D. Perspective insight and application of in silico tool as virtual screening method for lead designing and development. J Med Pharm allied Sci., 2021, 16-24.Moradi, M.; Golmohammadi, R.; Najafi, A. A contemporary review on the important role of in silico approaches for managing different aspects of COVID-19 crisis. Inform. Med. Unlocked, 2022, 28, 100862.Singh, E.; Khan, R.J.; Jha, R.K.; Amera, G.M.; Jain, M.; Singh, R.P.; Muthukumaran, J.; Singh, A.K. A comprehensive review on promising anti-viral therapeutic candidates identified against main protease from SARS-CoV-2 through various computational methods. J. Genet. Eng. Biotechnol., 2020, 18(1), 69. doi: 10.1186/s43141-020-00085-z PMID: 33141358Mishra, D.; Mishra, A.; Chaturvedi, V.K.; Singh, M.P. An overview of COVID-19 with an emphasis on computational approach for its preventive intervention 3 Biotech., 2020, 10(10), 435.Chopra, B.; Dhingra, A.K. Natural products: A lead for drug discovery and development. Phytother. Res., 2021, 35(9), 4660-4702. doi: 10.1002/ptr.7099 PMID: 33847440Newman, D.J.; Cragg, G.M. Natural products as sources of new drugs over the nearly four decades from 01/1981 to 09/2019. J. Nat. Prod., 2020, 83(3), 770-803. doi: 10.1021/acs.jnatprod.9b01285 PMID: 32162523Dewick, P.M. Medicinal natural products: A biosynthetic approach, 2nd Ed; John Wiley & Sons Ltd: Chichester, UK, 2002.de Leon, V.N.O.; Manzano, J.A.H.; Pilapil, D.Y.H., IV; Fernandez, R.A.T.; Ching, J.K.A.R.; Quimque, M.T.J.; Agbay, J.C.M.; Notarte, K.I.R.; Macabeo, A.P.G. Anti-HIV reverse transcriptase plant polyphenolic natural products with in silico inhibitory properties on seven non-structural proteins vital in SARS-CoV-2 pathogenesis. J. Genet. Eng. Biotechnol., 2021, 19(1), 104. doi: 10.1186/s43141-021-00206-2 PMID: 34272647Alhadrami, H.A.; Sayed, A.M.; Hassan, H.M.; Youssif, K.A.; Gaber, Y.; Moatasim, Y.; Kutkat, O.; Mostafa, A.; Ali, M.A.; Rateb, M.E.; Abdelmohsen, U.R.; Gamaleldin, N.M. Cnicin as an anti-SARS-COV-2: An integrated in silico and in vitro approach for the rapid identification of potential COVID-19 therapeutics. Antibiotics, 2021, 10(5), 542. doi: 10.3390/antibiotics10050542 PMID: 34066998Borquaye, LS; Gasu, EN; Ampomah, G.B; Kyei, L.K.; Amarh, M.A.; Mensah, C.N. Alkaloids from Cryptolepis sanguinolenta as potential inhibitors of SARS-CoV-2 viral proteins: An in silico study. Biomed Res Int., 2020, 2020.Nazir, M.; Tousif, M.I.; Khalid, M.; Parveen, S.; Akhter, N.; Farooq, N.; Khan, M.U.; Mehmood, R.F.; Mahomoodally, M.F.; Muhammad, S.; Alarfaji, S.S. Isolation of thioinosine and butenolides from a terrestrial actinomycetes sp. GSCW‐51 and their in silico studies for potential against SARS‐CoV‐2. Chem. Biodivers., 2022, 19(4), e202100843. doi: 10.1002/cbdv.202100843 PMID: 35213767Uras, I.S.; Korinek, M.; Albohy, A.; Abdulrazik, B.S.; Lin, W.; Ebada, S.S.; Konuklugil, B. Anti‐inflammatory, antiallergic and COVID‐19 main protease (Mpro) inhibitory activities of butenolides from a marine‐derived fungus Aspergillus costaricaensis. ChemistrySelect, 2022, 7(12), e202200130. doi: 10.1002/slct.202200130 PMID: 35599958Dogan, K.; Erol, E.; Didem Orhan, M.; Degirmenci, Z.; Kan, T.; Gungor, A.; Yasa, B.; Avsar, T.; Cetin, Y.; Durdagi, S.; Guzel, M. Instant determination of the artemisinin from various Artemisia annua L. extracts by LC‐ESI‐MS/MS and their in silico modelling and in vitro antiviral activity studies against SARS‐CoV‐2. Phytochem. Anal., 2022, 33(2), 303-319. doi: 10.1002/pca.3088 PMID: 34585460ElNaggar, M.H.; Abdelwahab, G.M.; Kutkat, O. GabAllah, M.; Ali, M.A.; El-Metwally, M.E.A.; Sayed, A.M.; Abdelmohsen, U.R.; Khalil, A.T. Aurasperone A inhibits SARS CoV-2 in vitro: An integrated in vitro and in silico study. Mar. Drugs, 2022, 20(3), 179. doi: 10.3390/md20030179 PMID: 35323478Mujwar, S.; Sun, L.; Fidan, O. In silico evaluation of food‐derived carotenoids against SARS‐COV‐2 drug targets: Crocin is a promising dietary supplement candidate for COVID ‐19. J. Food Biochem., 2022, 46(9), e14219. doi: 10.1111/jfbc.14219 PMID: 35545850Oh, E.; Wang, W.; Park, K.H.; Park, C.; Cho, Y.; Lee, J.; Kang, E.; Kang, H. (+)-Usnic acid and its salts, inhibitors of SARS‐CoV‐2, identified by using in silico methods and in vitro assay. Sci. Rep., 2022, 12(1), 13118. doi: 10.1038/s41598-022-17506-3 PMID: 35908082Makhoba, X.H.; Viegas, C., Jr; Mosa, R.A.; Viegas, F.P.D.; Pooe, O.J. Potential impact of the multi-target drug approach in the treatment of some complex diseases. Drug Des. Devel. Ther., 2020, 14, 3235-3249. doi: 10.2147/DDDT.S257494 PMID: 32884235Hossain, R.; Sarkar, C.; Hassan, S.M.H.; Khan, R.A.; Arman, M.; Ray, P.; Islam, M.T. Daştan, S.D.; Sharifi-Rad, J.; Almarhoon, Z.M.; Martorell, M.; Setzer, W.N.; Calina, D. In silico screening of natural products as potential inhibitors of SARS-COV-2 using molecular docking simulation. Chin. J. Integr. Med., 2022, 28(3), 249-256. doi: 10.1007/s11655-021-3504-5 PMID: 34913151Manabe, T.; Park, H.; Minami, T. Calcineurin-nuclear factor for activated T cells (NFAT) signaling in pathophysiology of wound healing. Inflamm. Regen., 2021, 41(1), 26. doi: 10.1186/s41232-021-00176-5 PMID: 34407893Pollard, C.A.; Morran, M.P.; Nestor-Kalinoski, A.L. The COVID-19 pandemic: A global health crisis. Physiol. Genom., 2020, 52(11), 549-557. doi: 10.1152/physiolgenomics.00089.2020 PMID: 32991251Junior, N.N.; Santos, I.A.; Meireles, B.A.; Nicolau, M.S.A.P.; Lapa, I.R.; Aguiar, R.S.; Jardim, A.C.G.; José, D.P. in silico evaluation of lapachol derivatives binding to the nsp9 of SARS-CoV-2. J. Biomol. Struct. Dyn., 2022, 40(13), 5917-5931. doi: 10.1080/07391102.2021.1875050 PMID: 33478342Albutti, A. Rescuing the host immune system by targeting the immune evasion complex ORF8-IRF3 in SARS-CoV-2 infection with natural products using molecular modeling approaches. Int. J. Environ. Res. Public Health, 2021, 19(1), 112. doi: 10.3390/ijerph19010112 PMID: 35010372Abdelkader, A.; Elzemrany, A.A.; El-Nadi, M.; Elsabbagh, S.A.; Shehata, M.A.; Eldehna, W.M.; El-Hadidi, M.; Ibrahim, T.M. In silico targeting of SARS-CoV-2 nsp6 for drug and natural products repurposing. Virology, 2022, 573, 96-110. doi: 10.1016/j.virol.2022.06.008 PMID: 35738174Panagiotopoulos, A.; Tseliou, M.; Karakasiliotis, I.; Kotzampasi, D.M.; Daskalakis, V.; Kesesidis, N.; Notas, G.; Lionis, C.; Kampa, M.; Pirintsos, S.; Sourvinos, G.; Castanas, E. p‐cymene impairs SARS‐CoV‐2 and Influenza A (H1N1) viral replication: In silico predicted interaction with SARS‐CoV‐2 nucleocapsid protein and H1N1 nucleoprotein. Pharmacol. Res. Perspect., 2021, 9(4), e00798. doi: 10.1002/prp2.798 PMID: 34128351Alibakhshi, A.; Ranjbar, M.M.; Javanmard, S.H.; Yarian, F.; Ahangarzadeh, S. Virtual screening for the identification of potential candidate molecules against Envelope (E) and Membrane (M) Proteins of SARS-CoV-2. J. Comput. Biophys. Chem., 2021, 20(3), 209-224. doi: 10.1142/S2737416521500083Srivastava, N.; Garg, P.; Srivastava, P.; Seth, P.K. A molecular dynamics simulation study of the ACE2 receptor with screened natural inhibitors to identify novel drug candidate against COVID-19. PeerJ, 2021, 9, e11171. doi: 10.7717/peerj.11171 PMID: 33981493Aatif, M.; Muteeb, G.; Alsultan, A.; Alshoaibi, A.; Khelif, B.Y. Dieckol and its derivatives as potential inhibitors of SARS-CoV-2 spike protein (UK Strain: VUI 202012/01): A computational study. Mar. Drugs, 2021, 19(5), 242. doi: 10.3390/md19050242 PMID: 33922914Narayanan, N.; Nair, D.T. Ritonavir may inhibit exoribonuclease activity of nsp14 from the SARS-CoV-2 virus and potentiate the activity of chain terminating drugs. Int. J. Biol. Macromol., 2021, 168, 272-278. doi: 10.1016/j.ijbiomac.2020.12.038 PMID: 33309661Kashyap, D.; Jakhmola, S.; Tiwari, D.; Kumar, R.; Moorthy, N.S.H.N.; Elangovan, M. Plant derived active compounds as potential anti SARS-CoV-2 agents: An in silico study. J. Biomol. Struct. Dyn., 2021, 1-22. PMID: 34225565Xu, C.; Ke, Z.; Liu, C.; Wang, Z.; Liu, D.; Zhang, L.; Wang, J.; He, W.; Xu, Z.; Li, Y.; Yang, Y.; Huang, Z.; Lv, P.; Wang, X.; Han, D.; Li, Y.; Qiao, N.; Liu, B. Systemic in silico screening in drug discovery for coronavirus disease (COVID-19) with an online interactive web server. J. Chem. Inf. Model., 2020, 60(12), 5735-5745. doi: 10.1021/acs.jcim.0c00821 PMID: 32786695Frye, L.; Bhat, S.; Akinsanya, K.; Abel, R. From computer-aided drug discovery to computer-driven drug discovery. Drug Discov. Today. Technol., 2021, 39, 111-117. doi: 10.1016/j.ddtec.2021.08.001 PMID: 34906321Adelusi, T.I.; Oyedele, A.Q.K.; Boyenle, I.D.; Ogunlana, A.T.; Adeyemi, R.O.; Ukachi, C.D. Molecular modeling in drug discovery. Inform. Med. Unlocked, 2022, 29, 100880. doi: 10.1016/j.imu.2022.100880Singh, N.; Rai, S.N.; Singh, V.; Singh, M.P. Molecular characterization, pathogen-host interaction pathway and in silico approaches for vaccine design against COVID-19. J. Chem. Neuroanat., 2020, 110, 101874. doi: 10.1016/j.jchemneu.2020.101874 PMID: 33091590Basu, S.; Ramaiah, S.; Anbarasu, A. In silico strategies to combat COVID-19: A comprehensive review. Biotechnol. Genet. Eng. Rev., 2021, 37(1), 64-81. doi: 10.1080/02648725.2021.1966920 PMID: 34470564Wnorowska, S.; Targowska-Duda, K.; Kurzepa, J.; Wnorowski, A.; Strzemski, M. Carlina oxide inhibits the interaction of SARS-CoV-2 S glycoprotein with angiotensinconverting enzyme 2 Ind. Crop. Prod., 2022, 187(Part A), 115338. doi: 10.1016/j.indcrop.2022.115338Shahhamzehei, N.; Abdelfatah, S.; Efferth, T. In silico and in vitro identification of pan-coronaviral main protease inhibitors from a large natural product library. Pharmaceuticals, 2022, 15(3), 308. doi: 10.3390/ph15030308 PMID: 35337106Wang, L.; Wu, Y.; Yao, S.; Ge, H.; Zhu, Y.; Chen, K.; Chen, W.; Zhang, Y.; Zhu, W.; Wang, H.; Guo, Y.; Ma, P.; Ren, P.; Zhang, X.; Li, H.; Ali, M.A.; Xu, W.; Jiang, H.; Zhang, L.; Zhu, L.; Ye, Y.; Shang, W.; Bai, F. Discovery of potential small molecular SARS-CoV-2 entry blockers targeting the spike protein. Acta Pharmacol. Sin., 2022, 43(4), 788-796. doi: 10.1038/s41401-021-00735-z PMID: 34349236Joshi, T.; Joshi, T.; Sharma, P.; Mathpal, S.; Pundir, H.; Bhatt, V.; Chandra, S. in silico screening of natural compounds against COVID-19 by targeting Mpro and ACE2 using molecular docking. Eur. Rev. Med. Pharmacol. Sci., 2020, 24(8), 4529-4536. PMID: 32373991Bhardwaj, A.; Sharma, S.; Singh, S.K. Molecular docking studies to identify promising natural inhibitors targeting SARS-CoV-2 nsp10-nsp16 protein complex. Turk. J. Pharm. Sci., 2022, 19(1), 93-100. doi: 10.4274/tjps.galenos.2021.56957 PMID: 35227055Chatterjee, A.; Basak, H.K.; Saha, S.; Ghosh, J.; Paswan, U.; Karmakar, S.; Pal, A. Sequence analysis, structure prediction of receptor proteins and in silico study of potential inhibitors for management of life threatening COVID-19. Lett. Drug Des. Discov., 2022, 19(2), 108-122. doi: 10.2174/1570180818666210804141613Negi, P.; Das, L.; Prakash, S.; Patil, V.M. Screening of Phytochemicals from Curcuma Longa for their inhibitory activity on SARS-CoV-2: An in-silico study. Antiinfect. Agents, 2022, 20(1), e190721194860. doi: 10.2174/2211352519666210719090130Erukainure, O.L.; Atolani, O.; Muhammad, A.; Katsayal, S.B.; Ebhuoma, O.O.; Ibeji, C.U.; Mesaik, M.A. Targeting the initiation and termination codons of SARS-CoV-2 spike protein as possible therapy against COVID-19: The role of novel harpagide 5-O-β-D-glucopyranoside from Clerodendrum volubile P Beauv. (Labiatae). J. Biomol. Struct. Dyn., 2022, 40(6), 2475-2488. doi: 10.1080/07391102.2020.1840439 PMID: 33140706Irfan, A.; Imran, M.; Mumtaz, M.W.; Raza Basra, M.A. Molecular docking and computational exploration of isolated drugs from daphne species against COVID-19. Iran J Chem Chem Eng., 2021, 40(6), 2019-2027.Wijaya, R.M.; Hafidzhah, M.A.; Kharisma, V.D.; Ansori, A.N.M.; Parikesit, A.A. COVID-19 in silico drug with Zingiber officinale natural product compound library targeting the mpro protein. Makara J. Sci., 2021, 25(3), 162-171.El-Hawary, S.S.; Mohammed, R.; Bahr, H.S.; Attia, E.Z.; El-Katatny, M.H.; Abelyan, N.; Al-Sanea, M.M.; Moawad, A.S.; Abdelmohsen, U.R. Soybean‐associated endophytic fungi as potential source for anti‐COVID‐19 metabolites supported by docking analysis. J. Appl. Microbiol., 2021, 131(3), 1193-1211. doi: 10.1111/jam.15031 PMID: 33559270Shaldam, M.A.; Yahya, G.; Mohamed, N.H.; Abdel-Daim, M.M.; Al Naggar, Y. in silico screening of potent bioactive compounds from honeybee products against COVID-19 target enzymes. Environ. Sci. Pollut. Res. Int., 2021, 28(30), 40507-40514. doi: 10.1007/s11356-021-14195-9 PMID: 33934306Naik, B.; Gupta, N.; Ojha, R.; Singh, S.; Prajapati, V.K.; Prusty, D. High throughput virtual screening reveals SARS-CoV-2 multi-target binding natural compounds to lead instant therapy for COVID-19 treatment. Int. J. Biol. Macromol., 2020, 160, 1-17. doi: 10.1016/j.ijbiomac.2020.05.184 PMID: 32470577Kapoor, N.; Ghorai, S.M.; Khuswaha, P.K.; Bandichhor, R.; Brogi, S. Butein as a potential binder of human ACE2 receptor for interfering with SARS-CoV-2 entry: A computer-aided analysis. J. Mol. Model., 2022, 28(9), 270. doi: 10.1007/s00894-022-05270-0 PMID: 36001177Shaji, D.; Yamamoto, S.; Saito, R.; Suzuki, R.; Nakamura, S.; Kurita, N. Proposal of novel natural inhibitors of severe acute respiratory syndrome coronavirus 2 main protease: Molecular docking and ab initio fragment molecular orbital calculations. Biophys. Chem., 2021, 275, 106608. doi: 10.1016/j.bpc.2021.106608 PMID: 33962341Loschwitz, J.; Jäckering, A.; Keutmann, M.; Olagunju, M.; Eberle, R.J.; Coronado, M.A. Novel inhibitors of the main protease enzyme of SARS-CoV-2 identified via molecular dynamics simulation-guided in vitro assay. Bioorg. Chem., 2020, 2021, 111. PMID: 33862474Rakshit, G.; Dagur, P.; Satpathy, S.; Patra, A.; Jain, A.; Ghosh, M. Flavonoids as potential therapeutics against novel coronavirus disease-2019 (nCOVID-19). J. Biomol. Struct. Dyn., 2022, 40(15), 6989-7001. doi: 10.1080/07391102.2021.1892529 PMID: 33682606Majumder, R.; Mandal, M. Screening of plant-based natural compounds as a potential COVID-19 main protease inhibitor: An in silico docking and molecular dynamics simulation approach. J. Biomol. Struct. Dyn., 2022, 40(2), 696-711. doi: 10.1080/07391102.2020.1817787 PMID: 32897138Bharadwaj, K.K.; Sarkar, T.; Ghosh, A.; Baishya, D.; Rabha, B.; Panda, M.K.; Nelson, B.R.; John, A.B.; Sheikh, H.I.; Dash, B.P.; Edinur, H.A.; Pati, S. Macrolactin A as a Novel Inhibitory Agent for SARS-CoV-2 Mpro: Bioinformatics Approach. Appl. Biochem. Biotechnol., 2021, 193(10), 3371-3394. doi: 10.1007/s12010-021-03608-7 PMID: 34212286Fadaka, A.O.; Sibuyi, N.R.S.; Martin, D.R.; Klein, A.; Madiehe, A.; Meyer, M. Development of effective therapeutic molecule from natural sources against coronavirus protease. Int. J. Mol. Sci., 2021, 22(17), 9431. doi: 10.3390/ijms22179431 PMID: 34502340Goyzueta-Mamani, L.D.; Barazorda-Ccahuana, H.L.; Mena-Ulecia, K.; Chávez-Fumagalli, M.A. Antiviral activity of metabolites from peruvian plants against Sars-Cov-2: An in silico approach. Molecules, 2021, 26(13), 3882. doi: 10.3390/molecules26133882 PMID: 34202092Vivek-Ananth, R.P.; Rana, A.; Rajan, N.; Biswal, H.S.; Samal, A. In silico identification of potential natural product inhibitors of human proteases key to SARS-CoV-2 Infection. Molecules, 2020, 25(17), 3822. doi: 10.3390/molecules25173822 PMID: 32842606Kumar, S.; Paul, P.; Yadav, P.; Kaul, R.; Maitra, S.S.; Jha, S.K. A multi-targeted approach to identify potential flavonoids against three targets in the SARS-CoV-2 life cycle. Comput. Biol. Med., 2022, 142, 105231. doi: 10.1016/j.compbiomed.2022.105231Ayipo, Y.O.; Ahmad, I.; Najib, Y.S.; Sheu, S.K.; Patel, H.; Mordi, M.N. 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., 2022, 1-19. doi: 10.1080/07391102.2022.2026818 PMID: 35037841Jha, P.; Singh, P.; Arora, S.; Sultan, A.; Nayek, A.; Ponnusamy, K.; Syed, M.A.; Dohare, R.; Chopra, M. Integrative multiomics and in silico analysis revealed the role of ARHGEF1 and its screened antagonist in mild and severe COVID‐19 patients. J. Cell. Biochem., 2022, 123(3), 673-690. doi: 10.1002/jcb.30213 PMID: 35037717Krieger, J.M.; Doruker, P.; Scott, A.L.; Perahia, D.; Bahar, I. Towards gaining sight of multiscale events: Utilizing network models and normal modes in hybrid methods. Curr. Opin. Struct. Biol., 2020, 64, 34-41. doi: 10.1016/j.sbi.2020.05.013 PMID: 32622329Giordano, D.; Biancaniello, C.; Argenio, M.A.; Facchiano, A. Drug design by pharmacophore and virtual screening approach. Pharmaceuticals, 2022, 15(5), 646. doi: 10.3390/ph15050646 PMID: 35631472Halimi, M.; Bararpour, P. Natural inhibitors of SARS-CoV-2 main protease: Structure based pharmacophore modeling, molecular docking and molecular dynamic simulation studies. J. Mol. Model., 2022, 28(9), 279. doi: 10.1007/s00894-022-05286-6 PMID: 36031629Ounissi, M.; Rachedi, F.Z. Targeting the SARS-CoV-2 Main Protease: in silico study contributed to exploring potential natural compounds as candidate inhibitors. JCBC, 2022, 21(6), 663-682. doi: 10.1142/S2737416522500272Augustin, T.L.; Hajbabaie, R.; Harper, M.T.; Rahman, T. Novel small-molecule scaffolds as candidates against the SARS Coronavirus 2 Main Protease: A fragment-guided in silico approach. Molecules, 2020, 25(23), 5501. doi: 10.3390/molecules25235501 PMID: 33255326Leelananda, S.P.; Lindert, S. Computational methods in drug discovery. Beilstein J. Org. Chem., 2016, 12, 2694-2718. doi: 10.3762/bjoc.12.267 PMID: 28144341Rao, S.J.A.; Shetty, N.P. Structure-based screening of natural product libraries in search of potential antiviral drug-leads as first-line treatment to COVID-19 infection. Microb. Pathog., 2022, 21, 105497. doi: 10.1016/j.micpath.2022.105497Eissa, I.H.; Khalifa, M.M.; Elkaeed, E.B.; Hafez, E.E.; Alsfouk, A.A.; Metwaly, A.M. in silico exploration of potential natural inhibitors against SARS-COV-2 nsp10. Molecules, 2021, 26(20), 6151. doi: 10.3390/molecules26206151 PMID: 34684735Jade, D.; Ayyamperumal, S.; Tallapaneni, V.; Joghee Nanjan, C.M.; Barge, S.; Mohan, S. Virtual high throughput screening: Potential inhibitors for SARS-CoV-2 PLPRO and 3CLPRO proteases. Eur. J. Pharmacol., 2020, 2021, 901. PMID: 33823185Alhadrami, H.A.; Sayed, A.M.; Al-Khatabi, H.; Alhakamy, N.A.; Rateb, M.E. Scaffold hopping of α-rubromycin enables direct access to FDA-approved cromoglicic acid as a SARS-COV-2 mpro inhibitor. Pharmaceuticals, 2021, 14(6), 541. doi: 10.3390/ph14060541 PMID: 34198933Marahatha, R.; Shrestha, A.; Sharma, K.; Regmi, B.P.; Sharma, K.R.; Poudel, P. In silico study of alkaloids: Neferine and berbamine potentially inhibit the SARS-CoV-2 RNA-dependent RNA. Polymerase. J. Chem., 2022.Jana, A.; Roy, T.; Layek, S.; Ghosal, S.; Banerjee, D.R. Computational investigation on natural quinazoline alkaloids as potential inhibitors of the main protease (Mpro) of SARS-CoV-2. J. Comput. Biophys. Chem., 2022, 21(1), 65-82. doi: 10.1142/S2737416522500053Wang, Z.; Belecciu, T.; Eaves, J.; Reimers, M.; Bachmann, M.H.; Woldring, D. Phytochemical drug discovery for COVID-19 using high-resolution computational docking and machine learning assisted binder prediction. J. Biomol. Struct. Dyn., 2022, 1-21. doi: 10.1080/07391102.2022.2112976 PMID: 35993534Ahmed, F.; Soomro, A.M.; Chethikkattuveli Salih, A.R.; Samantasinghar, A.; Asif, A.; Kang, I.S.; Choi, K.H. A comprehensive review of artificial intelligence and network based approaches to drug repurposing in COVID-19. Biomed. Pharmacother., 2022, 153, 113350. doi: 10.1016/j.biopha.2022.113350 PMID: 35777222Patel, V.; Shah, M. Artificial intelligence and machine learning in drug discovery and development. Intell. Med., 2022, 2(3), 134-140. doi: 10.1016/j.imed.2021.10.001Cong, Y.; Endo, T. Multi-omics and artificial intelligence-guided drug repositioning: Prospects, challenges, and lessons learned from COVID-19. OMICS, 2022, 26(7), 361-371. doi: 10.1089/omi.2022.0068 PMID: 35759424Pillai, N.; Dasgupta, A.; Sudsakorn, S.; Fretland, J.; Mavroudis, P.D. Machine Learning guided early drug discovery of small molecules. Drug Discov. Today, 2022, 27(8), 2209-2215. doi: 10.1016/j.drudis.2022.03.017 PMID: 35364270Nedyalkova, M.; Vasighi, M.; Sappati, S.; Kumar, A.; Madurga, S.; Simeonov, V. Inhibition ability of natural compounds on receptor-binding domain of SARS-CoV2: An in silico approach. Pharmaceuticals, 2021, 14(12), 1328. doi: 10.3390/ph14121328 PMID: 34959727Kadioglu, O.; Saeed, M.; Greten, H.J.; Efferth, T. Identification of novel compounds against three targets of SARS CoV-2 coronavirus by combined virtual screening and supervised machine learning. Comput. Biol. Med., 2021, 133, 104359. doi: 10.1016/j.compbiomed.2021.104359