Abstract
Approaches in disruption of MDM2-p53 interactions have now emerged as an important therapeutic strategy in resurrecting wild type p53 functional status. The present study highlights virtual screening strategies in identification of high affinity small molecule non-peptidic inhibitors. Nutlin3A and RG7112 belonging to compound class of Cis-imidazoline, MI219 of Spiro-oxindole class and Benzodiazepine derived TDP 665759 served as query small molecules for similarity search with a threshold of 95%. The query molecules and the similar molecules corresponding to each query were docked at the transactivation binding cleft of MDM2 protein. Aided by MolDock algorithm, high affinity compound against MDM2 was retrieved. Patch Dock supervised Protein-Protein interactions were established between MDM2 and ligand (query and similar) bound and free states of p53. Compounds with PubCid 68870345, 77819398, 71132874, and 11952782 respectively structurally similar to Nutlin3A, RG7112, Mi219 and TDP 665759 demonstrated higher affinity to MDM2 in comparison to their parent compounds. Evident from the protein-protein interaction studies, all the similar compounds except for 77819398 (similar to RG 7112) showed appreciable inhibitory potential. Of particular relevance, compound 68870345 akin to Nutlin 3A had highest inhibitory potential that respectively showed 1.3, 1.2, 1.16 and 1.26 folds higher inhibitory potential than Nutilin 3A, MI 219, RG 7112 and TDP 1665759. Compound 68870345 was further mapped for structure based pharamacophoric features. In the study, we report Cis-imidazoline derivative compound; Pubcid: 68870345 to have highest inhibitory potential in blocking MDM2-p53 interactions hitherto discovered.
Highlights
Since the discovery of p53 in 1979 (Lane et al, 1979; DeLeo et al, 1979; Linzer et al, 1979); it has surfaced as a most important tumor suppressor protein central to regulation of cell cycle, apoptosis, DNA repair, senescence, and angiogenesis (Vousden et al, 2002; Fridman et al, 2003; Teodor et al, 2007)
Approaches in disruption of MDM2-p53 interactions have emerged as an important therapeutic strategy in resurrecting wild type p53 functional status
Nutlin3A and RG7112 belonging to compound class of Cis-imidazoline, MI219 of Spiro-oxindole class and Benzodiazepine derived TDP 665759 served as query small molecules for similarity search with a threshold of 95%
Summary
Since the discovery of p53 in 1979 (Lane et al, 1979; DeLeo et al, 1979; Linzer et al, 1979); it has surfaced as a most important tumor suppressor protein central to regulation of cell cycle, apoptosis, DNA repair, senescence, and angiogenesis (Vousden et al, 2002; Fridman et al, 2003; Teodor et al, 2007). The pioneering studies by Oliner et al (1992) provided a convincing evidence of involvement of other regulatory proteins that encourages abnormal cell division. Potent and specific small-molecule inhibitors with desirable pharmaceutical properties to inhibit MDM2-p53 interactions such as Nutlin-3 (Vassilev et al, 2004) and MI-219 (Shangary et al, 2008) are available. Studies using these inhibitors in preclinical models have already provided strong evidence that targeting the MDM2-p53 interaction using small-molecule inhibitors is a promising cancer therapeutic approach (Vassilev et al, 2004; Patton et al, 2006; Tovar et al, 2006; Sarek et al, 2007). In the view of above, through virtual screening approaches, we sought to identify a novel compound as a substitute to the customary drugs anticipated having higher affinity against MDM2 protein and possibly having commendable potential in disrupting MDM-p53 interactions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callMore From: Asian Pacific journal of cancer prevention : APJCP
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
