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It is important to find effective antiviral drugs to combat SARS-CoV-2 and its variants. The main protease (M\n                      <jats:sup>pro<\/jats:sup>\n                      ) of SARS-CoV-2 is a promising therapeutic target due to its crucial role in viral replication and its conservation in all the variants. Therefore, the aim of this work was to identify an effective inhibitor of M\n                      <jats:sup>pro<\/jats:sup>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec sec-type=\"materials-methods\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      We studied around 200 antimicrobial peptides using\n                      <jats:italic toggle=\"yes\">in silico<\/jats:italic>\n                      methods including molecular docking and allergenicity and toxicity prediction. One selected antiviral peptide was studied experimentally using a Bioluminescence Resonance Energy Transfer (BRET)-based M\n                      <jats:sup>pro<\/jats:sup>\n                      biosensor, which reports M\n                      <jats:sup>pro<\/jats:sup>\n                      activity through a decrease in energy transfer.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec sec-type=\"results\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Molecular docking identified one natural antimicrobial peptide, Protegrin-2, with high binding affinity and stable interactions with M\n                      <jats:sup>pro<\/jats:sup>\n                      allosteric residues. Furthermore, free energy calculations and molecular dynamics simulation illustrated a high affinity interaction between the two. We also determined the impact of the binding of Protegrin-2 to M\n                      <jats:sup>pro<\/jats:sup>\n                      using a BRET-based assay, showing that it inhibits the proteolytic cleavage activity of M\n                      <jats:sup>pro<\/jats:sup>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec sec-type=\"conclusion\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Our\n                      <jats:italic toggle=\"yes\">in silico<\/jats:italic>\n                      and experimental studies identified Protegrin-2 as a potent inhibitor of M\n                      <jats:sup>pro<\/jats:sup>\n                      that could be pursued further towards drug development against COVID-19 infection.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1016\/j.csbj.2023.07.020","type":"journal-article","created":{"date-parts":[[2023,7,24]],"date-time":"2023-07-24T20:07:50Z","timestamp":1690229270000},"page":"3665-3671","update-policy":"https:\/\/doi.org\/10.1016\/elsevier_cm_policy","source":"Crossref","is-referenced-by-count":12,"title":["Protegrin-2, a potential inhibitor for targeting SARS-CoV-2 main protease M\n                    <sup>pro<\/sup>"],"prefix":"10.34133","volume":"21","author":[{"given":"Zainab","family":"Jan","sequence":"first","affiliation":[{"name":"Division of Genomics and Translational Biomedicine, College of Health & Life Sciences, Hamad Bin Khalifa University, Education City, Qatar Foundation, Doha 34110, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anupriya M.","family":"Geethakumari","sequence":"additional","affiliation":[{"name":"Division of Biological and Biomedical Sciences, College of Health & Life Sciences, Hamad Bin Khalifa University, Education City, Qatar Foundation, Doha 34110, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kabir H.","family":"Biswas","sequence":"additional","affiliation":[{"name":"Division of Biological and Biomedical Sciences, College of Health & Life Sciences, Hamad Bin Khalifa University, Education City, Qatar Foundation, Doha 34110, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Puthen Veettil","family":"Jithesh","sequence":"additional","affiliation":[{"name":"Division of Genomics and Translational Biomedicine, College of Health & Life Sciences, Hamad Bin Khalifa University, Education City, Qatar Foundation, Doha 34110, Qatar"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"221","published-online":{"date-parts":[[2023,7,25]]},"reference":[{"key":"e_1_3_5_2_2","doi-asserted-by":"publisher","DOI":"10.1111\/1751-7915.14064"},{"key":"e_1_3_5_3_2","doi-asserted-by":"publisher","DOI":"10.1002\/jmv.27588"},{"key":"e_1_3_5_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/s13238-021-00883-2"},{"key":"e_1_3_5_5_2","doi-asserted-by":"crossref","first-page":"780","DOI":"10.1021\/acsptsci.0c00059","article-title":"The potential of antimicrobial peptides as an antiviral therapy against COVID-19","volume":"3","author":"Elnagdy S.","year":"2020","unstructured":"Elnagdy S. and AlKhazindar M.: The potential of antimicrobial peptides as an antiviral therapy against COVID-19. 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