Molecular investigation of the dual inhibition mechanism for targeted P53 regulator MDM2/MDMX inhibitors

• DOI: 10.1039/d2cp01780f
• Publication Date: 2022-06-21T00:41:23Z
• Authors: Xiaoyu Zhao; Danyang Xiong; Song Luo; Lili Duan
• Keywords: MDMX; Alanine scanning

Inhibitors that competitively bind MDM2/MDMX can block the inhibition of P53 by and restart its tumor-suppressive effect. Molecular studies targeting inhibitors have always been a hot topic in anticancer drug design. Although numerous designed previously against MDM2/MDMX, their dual efficacy has not demonstrated, few assessed general causes affecting these inhibitors. Here, molecular dynamics simulations alanine scanning combined with interaction entropy method were employed to precisely investigate whether 16 could dually inhibit similarities differences modes. Thereby addressing key residue sites inhibition. Residues L54/M53, I61/60, M62/61, Y67/66, V93/92 which are corresponding positions both protein structures, provide significant conditions for tightly. In addition, most prefer MDM2 than MDMX, residues H96 I99 attractive targets inhibitors, resulting binding different affinity. These should be considered development For inhibitory potential based on affinity complexes. Still, it is questionable they exert excellent considering assessment hot-spots. At least MDMX superior due difference energy van der Waals interactions at sites. Furthermore, analysis three representative (TUZ/HRH HRQ preferences MDM2/MDMX), 3-chloropyridine TUZ leads differential between inhibitor MDM2/MDMX. It readily forms hydrophobic surrounding I99. But this phenomenon does occur TUZ-MDMX system, implying critical role H96/P95 I99/L98. And completely mechanism explains inability well. Thus, we cautious about ability. Besides, HRH more prone strong whereas 2-chlorofluorobenzene detrimental this. We hope findings will reliable insights screening optimization