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We envisioned that the \u2018dual\u2010site\u2019\u2010binding of Bcl2 has significant prospects and paves the way for the next round of rational design of potent Waldenstr\u00f6m macroglobulinemia (WM) therapy. The preferential binding mechanisms of the multi\u2010catalytic sites of the Bcl2 enzyme have been a subject of debate in the literature. This study conducted a systematic procedure to explore the preferred binding modes and the structural effects of co\u2010binding at each catalytic active site. Interestingly, a mutual enhanced binding effect was observed \u2013 Venetoclax increased the binding affinity of JQ1 by 11.5\u2009%, while JQ1 boosted the binding affinity of Venetoclax by 16.3\u2009% when compared with individual inhibition of each drug. This synergistic binding effect has significantly increased protein stability, with substantial correlated movements and multiple van der Waals interactions. The structural and thermodynamic insights unveiled in this report would assist the future design of improved combined therapy against WM.<\/jats:p>","DOI":"10.1002\/cbdv.202100845","type":"journal-article","created":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T02:10:43Z","timestamp":1653444643000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Co\u2010Binding of JQ1 and Venetoclax Exhibited Synergetic Inhibitory Effect for Cancer Therapy; Potential Line of Treatment for the Waldenstr\u00f6m Macroglobulinemia Lymphoma"],"prefix":"10.1002","volume":"19","author":[{"given":"Ghazi","family":"Elamin","sequence":"first","affiliation":[{"name":"Molecular Bio-computation and Drug Design Laboratory School of Health Sciences University of KwaZulu-Natal, Westville Campus  Durban 4001 South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aimen","family":"Aljoundi","sequence":"additional","affiliation":[{"name":"Molecular Bio-computation and Drug Design Laboratory School of Health Sciences University of KwaZulu-Natal, Westville Campus  Durban 4001 South Africa"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8711-7783","authenticated-orcid":false,"given":"Mahmoud E. 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