Comparative modeling, comparative molecular docking analyses, and revealing of potential binding pockets of MDM-2: A candidate cancer gene

Abstract

MDM-2 is also known as E3 ubiquitin-protein ligase encoded by Mdm-2. MDM-2 is an important negative regulator of p53 tumor suppressor and performs key function as an inhibitor of p53 transcriptional activation and E3 ubiquitin ligase. MDM-2 also plays significant role in human cancers and therapeutic target. Hundred different structures were predicted through comparative modeling, threading and ab initio approaches followed by the evaluation of predicted structures through various evaluation tools including ERRAT, ProSa-web, Rampage, molprobidity, verify3D and Anolea. The selected 3D structure of MDM-2 showed 13 α- helix chains, 2 β-pleated sheets along with 97.4468% overall quality factor of the predicted structure. Interestingly, it was observed that only 4.5% residues were present in outlier region and the observed errors were fixed. Moreover, 91.1% residues of the selected structure were present in favored region and 8.9% in allowed region having -6.0 Z-score. High throughput virtual screening and comparative molecular docking studies was performed. Four novel compounds have been reported that showed minimum binding energy (-8.1 Kcal/mol) and maximum binding affinity against MDM-2. Molecular docking analyses revealed that Ser154, Arg155, Pro156, Ser157, Lys185, Ser186, Ser188, Ser190, Ile189, Val247, Glu257, Asp173, Glu174, Glu178, Arg161, Ard181, Lys182, Arg183 and His184 residues are significant residues for therapeutic drug targets. The reported compounds showed effective energy scores. In addition, the site-directed mutagenesis may be helpful for further analyses. The reported compounds may act like potent drug compounds against MDM-2.