{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T16:00:05Z","timestamp":1791907205823,"version":"4.3.4"},"reference-count":92,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2023,1,22]],"date-time":"2023-01-22T00:00:00Z","timestamp":1674345600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Background, Aims, Methods, Results, Conclusions: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global challenge due to its ability to mutate into variants that spread more rapidly than the wild-type virus. The molecular biology of this virus has been extensively studied and computational methods applied are an example paradigm for novel antiviral drug therapies. The rapid evolution of SARS-CoV-2 in the human population is driven, in part, by mutations in the receptor-binding domain (RBD) of the spike (S-) protein, some of which enable tighter binding to angiotensin-converting enzyme (ACE2). More stable RBD-ACE2 association is coupled with accelerated hydrolysis by proteases, such as furin, trypsin, and the Transmembrane Serine Protease 2 (TMPRSS2) that augment infection rates, while inhibition of the 3-chymotrypsin-like protease (3CLpro) can prevent the viral replication. Additionally, non-RBD and non-interfacial mutations may assist the S-protein in adopting thermodynamically favorable conformations for stronger binding. This study aimed to report variant distribution of SARS-CoV-2 across European Union (EU)\/European Economic Area (EEA) countries and relate mutations with the driving forces that trigger infections. Variants\u2019 distribution data for SARS-CoV-2 across EU\/EEA countries were mined from the European Centre for Disease Prevention and Control (ECDC) based on the sequence or genotyping data that are deposited in the Global Science Initiative for providing genomic data (GISAID) and The European Surveillance System (TESSy) databases. Docking studies performed with AutoDock VINA revealed stabilizing interactions of putative antiviral drugs, e.g., selected anionic imidazole biphenyl tetrazoles, with the ACE2 receptor in the RBD-ACE2 complex. The driving forces of key mutations for Alpha, Beta, Gamma, Delta, Epsilon, Kappa, Lambda, and Omicron variants, which stabilize the RBD-ACE2 complex, were investigated by computational approaches. Arginine is the critical amino acid in the polybasic furin cleavage sites S1\/S2 (681-PRRARS-686) S2\u2032 (814-KRS-816). Critical mutations into arginine residues that were found in the delta variant (L452R, P681R) and may be responsible for the increased transmissibility and morbidity are also present in two widely spreading omicron variants, named BA.4.6 and BQ.1, where mutation R346T in the S-protein potentially contributes to neutralization escape. Arginine binders, such as Angiotensin Receptor Blockers (ARBs), could be a class of novel drugs for treating COVID-19.<\/jats:p>","DOI":"10.3390\/v15020309","type":"journal-article","created":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T03:26:41Z","timestamp":1674444401000},"page":"309","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Molecular Epidemiology of SARS-CoV-2: The Dominant Role of Arginine in Mutations and Infectivity"],"prefix":"10.3390","volume":"15","author":[{"given":"Harry","family":"Ridgway","sequence":"first","affiliation":[{"name":"Institute for Sustainable Industries and Liveable Cities, Victoria University, Melbourne 8001, VIC, Australia"},{"name":"AquaMem Consultants, Rodeo, NM 88056, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4189-5803","authenticated-orcid":false,"given":"Charalampos","family":"Ntallis","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8728-6245","authenticated-orcid":false,"given":"Christos T.","family":"Chasapis","sequence":"additional","affiliation":[{"name":"Institute of Chemical Biology, National Hellenic Research Foundation, 11635 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Konstantinos","family":"Kelaidonis","sequence":"additional","affiliation":[{"name":"NewDrug PC, Patras Science Park, 26504 Patras, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4642-8163","authenticated-orcid":false,"given":"Minos-Timotheos","family":"Matsoukas","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of West Attica, Egaleo, 12210 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panagiotis","family":"Plotas","sequence":"additional","affiliation":[{"name":"Laboratory of Primary Health Care, School of Health Rehabilitation Sciences, University of Patras, 26504 Patras, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6788-2771","authenticated-orcid":false,"given":"Vasso","family":"Apostolopoulos","sequence":"additional","affiliation":[{"name":"Institute for Health and Sport, Victoria University, Melbourne 3030, VIC, Australia"},{"name":"Immunology Program, Australian Institute for Musculoskeletal Science (AIMSS), Melbourne 3021, VIC, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graham","family":"Moore","sequence":"additional","affiliation":[{"name":"Pepmetics Inc., 772 Murphy Place, Victoria, BC V6Y 3H4, Canada"},{"name":"Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0463-4321","authenticated-orcid":false,"given":"Sotirios","family":"Tsiodras","sequence":"additional","affiliation":[{"name":"4th Department of Internal Medicine, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6167-7152","authenticated-orcid":false,"given":"Dimitrios","family":"Paraskevis","sequence":"additional","affiliation":[{"name":"Department of Hygiene Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, 11527 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5309-992X","authenticated-orcid":false,"given":"Thomas","family":"Mavromoustakos","sequence":"additional","affiliation":[{"name":"Department of Chemistry, National and Kapodistrian University of Athens, 11571 Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5554-2964","authenticated-orcid":false,"given":"John M.","family":"Matsoukas","sequence":"additional","affiliation":[{"name":"NewDrug PC, Patras Science Park, 26504 Patras, Greece"},{"name":"Institute for Health and Sport, Victoria University, Melbourne 3030, VIC, Australia"},{"name":"Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 1N4, Canada"},{"name":"Department of Chemistry, University of Patras, 26504 Patras, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,1,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Tian, D., Nie, W., Sun, Y., and Ye, Q. 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