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This work aims to find compounds from DrugBank that can modulate the stability of the spike RBD\u2010ACE2 protein\u2010protein complex. Employing a therapeutic repurposing strategy, we conducted molecular docking of over 9000\u2005DrugBank compounds against the Spike RBD\u2010ACE2 complex, on ten variants, including the wild\u2010type. We also evaluated the intricate stability of the RBD\u2010ACE2 proteins by molecular dynamics simulations, hydrogen bond analysis, RMSD analysis, radius of gyration analysis, and the QM\u2010MM approach. We assessed the efficacy of the top ten candidates for each variant as an inhibitor. Our findings demonstrated for the first time that DrugBank small molecules can interact in three distinct modalities inside the extensive protein\u2010protein interface of RBD and ACE2 complexes. The top ten analyses identified specific DrugBank candidates for each variant and molecules capable of binding to multiple variants. This comprehensive computational technique enables the screening and forecasting of hits for any big and shallow protein\u2010protein interface drug targets.<\/jats:p>","DOI":"10.1002\/cphc.202400751","type":"journal-article","created":{"date-parts":[[2024,12,7]],"date-time":"2024-12-07T08:48:38Z","timestamp":1733561318000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Modes of Binding of Small Molecules Dictate the Interruption of RBD\u2010ACE2 Complex of SARS\u2010CoV\u20102"],"prefix":"10.1002","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-1542-2005","authenticated-orcid":false,"given":"Sithanantham","family":"Muneeswaran","sequence":"first","affiliation":[{"name":"Chemical Biology and Biophysics Laboratory Department of Physical Chemistry School of Chemistry Madurai Kamaraj University  Palkalai Nagar Madurai Tamil Nadu India 625 021"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karuppiah Muruga","family":"Poopathi Raja","sequence":"additional","affiliation":[{"name":"Chemical Biology and Biophysics Laboratory Department of Physical Chemistry School of Chemistry Madurai Kamaraj University  Palkalai Nagar Madurai Tamil Nadu India 625 021"},{"name":"Chemical Biology and Biophysics Laboratory Department of Chemistry School of Physical Sciences Central University of Kerala  Sabarmati Building, Tejaswini Hills Periye, Kasaragod District Kerala India 671 320"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2024,12,19]]},"reference":[{"key":"e_1_2_9_1_1","doi-asserted-by":"publisher","DOI":"10.3390\/md19050242"},{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1021\/acsomega.3c00205"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules27061773"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-020-0820-9"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1080\/07391102.2020.1777901"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(03)13036-X"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/B978-0-12-803309-8.00002-1"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-020-74715-4"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1021\/acs.jctc.0c00063"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3000003"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.3390\/cimb44070208"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molstruc.2022.133032"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41579-020-00459-7"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9041131"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.sjbs.2020.11.049"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijbiomac.2022.01.059"},{"key":"e_1_2_9_17_1","doi-asserted-by":"crossref","unstructured":"S.\u2005L. 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