Discovery of novel dual inhibitors against Mdm2 and Mdmx proteins by in silico approaches and binding assay

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• 作者：Sahand Golestanian^a ; ¹ ; Amirhossein Sharifi^a ; ¹ ; Grzegorz M. Popowicz^b ; Homa Azizian^c ; Alireza Foroumadi^a ; Aleksandra Szwagierczak^b ; Tad A. Holak^b ; ^{holak@biochem.mpg.de" class="auth_mail" title="E-mail the corresponding author} ; Massoud Amanlou^a ; ^{amanlou@tums.ac.ir" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Dual inhibitors ; Mdm2 & Mdmx ; Drug design ; p53 ; In silico process ; Qualitative SAR
• 刊名：Life Sciences
• 出版年：2016
• 出版时间：15 January 2016
• 年：2016
• 卷：145
• 期：Complete
• 页码：240-246
• 全文大小：1210 K

文摘

The p53 protein, also called guardian of the genome, has a key role in cell cycle regulation. It is activated under stressful circumstances, such as DNA damage which results in permanent arrest or cell death. The protein is disabled in several types of human cancer due to over-expression of the two regulators, Mdm2 and Mdmx. As a result, inhibiting Mdm subtypes could reactivate p53 and bring about a promising therapeutic strategy in cancers.

Main methods

Here a structure-based pharmacophore search and docking simulation are presented in order to filter our in-house library which contains 1035 compounds to find novel scaffolds that inhibit Mdm2 and Mdmx concomitantly. Afterwards, fluorescence polarization binding assay was used to obtain inhibition constant of final compounds.

Key findings

Thirty two ligands were introduced to bioassay as a result of in-silico methods. Twelve of them inhibit both proteins with almost balanced K_i value ranging from 18 to 162 μM for Mdm2 and 18 to 233 μM for Mdmx. It was observed that all compounds fill Phe19 and Trp23 pockets of Mdm2/x binding sites and form a hydrogen bond with Trp23 pocket's neighbor amino acids in a manner similar to p53 protein. Additionally, it was concluded that Trp23 pocket of Mdmx has a bigger hydrophobic volume comparing with the one of Mdm2.

Significance

Three structure–activity relationship patterns are supposed which one of them presents usefulness features and can be used in future studies. This study presents first qualitative SAR for dual inhibitors against Mdm2/x.