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Here, we identify five highly potent inhibitors of MDM2 (termed as WY 1\u20135) that display significant inhibitory effects on MDM2\u2010p53 interaction by using a combined strategy of pharmacophore modeling, virtual screening, and molecular docking studies. Among them, WY\u20105 is the most active MDM2 inhibitor with an IC<jats:sub>50<\/jats:sub> value of 14.1\u00b12.8\u2005nM. Moreover, WY\u20105 significantly up\u2010regulate the protein level of p53 in SK\u2010Hep\u20101 cells harboring wild\u2010type p53. <jats:italic>In vitro<\/jats:italic> anticancer study reveals that WY\u20105 markedly inhibits the survival of SK\u2010Hep\u20101 cells. <jats:italic>In vivo<\/jats:italic> anticancer study suggests that WY\u20105 significantly inhibits the growth of SK\u2010Hep\u20101 cells\u2010derived xenograft in nude mice, with no observable toxicity. Our results demonstrate that WY\u20105 may be a promising candidate for the treatment of cancer harboring wild\u2010type p53.<\/jats:p>","DOI":"10.1002\/cmdc.202100517","type":"journal-article","created":{"date-parts":[[2021,11,21]],"date-time":"2021-11-21T22:29:30Z","timestamp":1637533770000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["The Discovery of Potential MDM2 Inhibitors: A Combination of Pharmacophore Modeling, Virtual Screening, Molecular Docking Studies, and <i>in\u2005vitro\/in\u2005vivo<\/i> Biological Evaluation"],"prefix":"10.1002","volume":"17","author":[{"given":"Xuelin","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Pharmacy The First People's Hospital of Chongqing Liang Jiang New Area  Chongqing 401121 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunqiao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pharmacy The First People's Hospital of Chongqing Liang Jiang New Area  Chongqing 401121 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Pharmacology Chongqing Medical University  Chongqing 400016 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hailin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacy The First People's Hospital of Chongqing Liang Jiang New Area  Chongqing 401121 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Song","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy The First People's Hospital of Chongqing Liang Jiang New Area  Chongqing 401121 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaoli","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Pharmacy The First People's Hospital of Chongqing Liang Jiang New Area  Chongqing 401121 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8892-2285","authenticated-orcid":false,"given":"Hu","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Pharmacy The First People's Hospital of Chongqing Liang Jiang New Area  Chongqing 401121 China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,12]]},"reference":[{"key":"e_1_2_7_1_1","doi-asserted-by":"publisher","DOI":"10.3390\/molecules24234386"},{"key":"e_1_2_7_2_1","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2013-0457"},{"key":"e_1_2_7_3_1","doi-asserted-by":"publisher","DOI":"10.1097\/00001622-200201000-00015"},{"key":"e_1_2_7_4_1","first-page":"4023","volume":"58","author":"Hussain S. 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