key: cord-310803-iig414jg authors: Khazeei Tabari, Mohammad Amin; Khoshhal, Hooman; Tafazoli, Alireza; Khandan, Mohanna; Bagheri, Abouzar title: Applying Computer Simulations in Battling with COVID-19, using pre-analyzed molecular and chemical data to face the pandemic date: 2020-10-17 journal: Inform Med Unlocked DOI: 10.1016/j.imu.2020.100458 sha: doc_id: 310803 cord_uid: iig414jg Coronavirus disease 2019 (COVID-19) has made many concerns for healthcare services especially, in finding useful therapeutic(s). Despite the scientists’ struggle to find and/or creating possible drugs, so far there is no treatment with high efficiency for the disease. During the pandemic, researchers have performed some molecular analyses to find potential therapeutics out of both the natural and synthetic available medicines. Computer simulations and related data have shown a significant role in drug discovery and development before. In this field, antiviral drugs, phytochemicals, anti-inflammatory agents, etc. were essential groups of compounds tested against COVID-19, using molecular modeling, molecular dynamics (MD), and docking tools. The results indicate promising effects of such compounds to be used in further experimental and clinical trials; Chloroquine, Chloroquine-OH, and Umifenovir as viral entry inhibitors, Remdesivir, Ribavirin, Lopinavir, Ritonavir, and Darunavir as viral replication inhibitors, and Sirolimus are the examples, which were tested clinically on patients after comprehensive assessments of the available data on molecular simulation. This review summarizes the outcomes of various computer simulations data in the battle against COVID-19 Coronaviruses (CoVs) are major respiratory disease pathogens. They are single-stranded 2 RNA viruses (+ ssRNA) and could be found in various animal species [1] . CoVs transmit from 3 other species to humans and cause mild to severe types of disorders [2] . Recently a kind of CoV 4 family, called SARS-CoV-2, has become pandemic worldwide, made a global concern for all 5 societies [3] . It is the third pathogenic and transmittable virus after previous outbreaks for this 6 family, including severe acute respiratory syndrome (SARS) and the Middle East respiratory 7 syndrome (MERS). Finding any effective treatment to prevent an epidemic/pandemic difficulty 8 is necessary for such situations [4] . COVID-19 is a disorder caused by SARS-CoV-2, which has CoV-2 genome sequencing demonstrated that ORF1a/b is closely similar to those from the bat, 4 civet, and other human SARS-CoVs, but the external sub-domain amino acid sequence of the 5 spike receptor-binding domain for this novel virus is only 40% similar to other SARS-related 6 coronaviruses. SARS-CoV-2's new ORF8 encodes a secretory protein with an alpha-helix, 7 following a six-strand beta-sheet. It was also shown that ORF3b encodes a new short protein 8 comparing to other CoVs. The 5′-and 3′-UTR sequences are identical to other β-CoVs in more 9 than 83.5% [8] . 10 To find the origin of SARS-CoV-2, two separate cDNA pools were utilized for genomic 11 sequence comparison; one from the Carassius auratus cell line and the other one from 12 Ctenopharyngodon idella head kidney tissue. Translated nucleotide BLAST (TBLASTN) 13 analysis revealed two cDNA clones (one from each pool) were remarkably similar to SARS-like-14 coronaviruses. The first clone included 152 amino acids that covered 2% of the SARS-CoV-2 15 genome and was 93.42% equal. The second also encompassed an 88 amino acid sequence, which 16 covered 1% of the SARS-CoV-2 genome with 93.18% equality. Therefore SARS-like-17 coronaviruses are general environmental pathogens that may even originate from lentic regions NSPs that play a role in viral replication and translation procedures [8] . CoV spike protein is a Class I fusion protein of CoVs [11] , which are considered as an 4 essential factor in host cell recognition [12] . The spike protein contains S1-S2 heterodimers that 5 bind to angiotensin-converting enzyme 2 (ACE2) in the human body [ heptad-repeat 1 and 2, transmembrane, and cytoplasmic domains. S1 and S2 subunits 12 demonstrate 70 and 99% similarity with two bat SARS-like CoVs (SL-CoVZXC21 and ZC45) 13 and other human SARS-CoVs [8] . 14 Also, the binding energy of the SARS-CoV-2 spike protein to ACE2 (-15.7 kcal/mol) is 15 higher than SARS-CoV (-14.1 kcal/mol). Therefore, SARS-CoV-2 can make more protein- The analyses showed nine non-toxic compounds with an ability to be formulated as drugs and Macaflavanone-E, and Vibsanol-B (isolated from Belamcanda chinensis, Macaranga tanarius, 13 and Viburnum odoratissimum respectively) caused a reduction in SARS-CoV-2 E-protein's 14 functional activity with higher binding affinity than other compounds. Two amino acids, 15 including VAL25 and PHE26, showed a strong interaction with these three phytochemicals. J o u r n a l P r e -p r o o f Synthetic Natural Depression of SARS-COV associated 3a protein Distraction of interaction between SARS-COV spike protein and ACE2 Case of the index patient who 1 caused tertiary transmission of COVID-19 infection in Korea: the application of 2 lopinavir/ritonavir for the treatment of COVID-19 infected pneumonia monitored by 3 quantitative RT-PCR Nelfinavir was predicted to be a potential 5 inhibitor of 2019-nCov main protease by an integrative approach combining homology 6 modelling, molecular docking and binding free energy calculation protease cleaves its C-terminal autoprocessing site by novel subsite cooperativity Protease Inhibitors as Antiviral Agents Achilles blind docking server Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir against SARS-CoV-2 15 RNA dependent RNA polymerase (RdRp): A molecular docking study Anti-HCV, nucleotide inhibitors, repurposing against COVID-19 Computational 20 approach towards understanding structural and functional role of cytokinin 21 oxidase/dehydrogenase 2 (CKX2) in enhancing grain yield in rice plant Structural and molecular modelling studies 24 reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 25 infection Sialic Acid Receptors of Viruses Network-based drug repurposing 29 for novel coronavirus 2019-nCoV/SARS-CoV-2 bcl-x, a bcl-31 2-related gene that functions as a dominant regulator of apoptotic cell death The role of c-jun protein in 34 proliferation and apoptosis of the endometrium throughout the menstrual cycle Inflammatory responses and 37 inflammation-associated diseases in organs Adjuvant treatment 40 with a mammalian target of rapamycin inhibitor, sirolimus, and steroids improves outcomes in 41 patients with severe H1N1 pneumonia and acute respiratory failure Emodin inhibits current through SARS-44 associated coronavirus 3a protein Emodin blocks the SARS coronavirus 46 spike protein and angiotensin-converting enzyme 2 interaction Thiopurine analogue inhibitors of severe 1 acute respiratory syndrome-coronavirus papain-like protease, a deubiquitinating and 2 deISGylating enzyme A pneumonia outbreak 4 associated with a new coronavirus of probable bat origin Activation of the c-Jun NH 2-terminal kinase pathway by 7 coronavirus infectious bronchitis virus promotes apoptosis independently of c-Jun Melatonin: 10 new insights on its therapeutic properties in diabetic complications Interaction between RAAS inhibitors and ACE2 in the context of 13 COVID-19 A Next 15 Generation Connectivity Map: L1000 Platform and the First 1,000,000 Profiles Repurposing didanosine as a potential treatment for COVID-19 using scRNA-18 seq data Repurposing Didanosine as a Potential Treatment for COVID-19 Using Single-Cell 20 RNA Sequencing Data Didanosine Indazolylamino 23 quinazolines and pyridopyrimidines as inhibitors of the EGFr and C-erbB-2 26 "Topoisomerase I-mediated inhibition of hypoxia-inducible factor 1: mechanism and therapeutic 27 implications Ro 90-7501 Is a Novel 29 Radiosensitizer for Cervical Cancer Cells that Inhibits ATM Phosphorylation Diagnosis of Alzheimer's disease utilizing amyloid and 32 tau as fluid biomarkers Global research on coronavirus disease (COVID-19) Model Database SWISS-40 MODEL: homology modelling of protein structures and complexes SWISS-MODEL: 43 modelling protein tertiary and quaternary structure using evolutionary information UniProt: a worldwide hub of protein knowledge Chloroquine dosing recommendations for pediatric COVID-19 2 supported by modeling and simulation Identification of Potential Binders of the Main 4 Protease 3CL(pro) of the COVID-19 via Structure-Based Ligand Design and Molecular Modeling Optimizing hydroxychloroquine dosing for patients with COVID-19: An integrative modeling 8 approach for effective drug repurposing Pharmacologic treatments for 10 coronavirus disease 2019 (COVID-19): a review This study was supported by Molecular and Cell Biology Research Center, Mazandaran University of Medical Sciences, Sari, Iran (Grant number: 7640).