Background: Approaches in disruption of MDM2-p53 interactions have now emerged as an importanttherapeutic strategy in resurrecting wild type p53 functional status. The present study highlights virtual screeningstrategies in identification of high affinity small molecule non-peptidic inhibitors. Nutlin3A and RG7112 belongingto compound class of Cis-imidazoline, MI219 of Spiro-oxindole class and Benzodiazepine derived TDP 665759served as query small molecules for similarity search with a threshold of 95%. The query molecules and thesimilar 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 supervisedProtein-Protein interactions were established between MDM2 and ligand (query and similar) bound and freestates of p53. Compounds with PubCid 68870345, 77819398, 71132874, and 11952782 respectively structurallysimilar to Nutlin3A, RG7112, Mi219 and TDP 665759 demonstrated higher affinity to MDM2 in comparison totheir parent compounds. Evident from the protein-protein interaction studies, all the similar compounds exceptfor 77819398 (similar to RG 7112) showed appreciable inhibitory potential. Of particular relevance, compound68870345 akin to Nutlin 3A had highest inhibitory potential that respectively showed 1.3, 1.2, 1.16 and 1.26folds higher inhibitory potential than Nutilin 3A, MI 219, RG 7112 and TDP 1665759. Compound 68870345 wasfurther mapped for structure based pharamacophoric features. In the study, we report Cis-imidazoline derivativecompound; Pubcid: 68870345 to have highest inhibitory potential in blocking MDM2-p53 interactions hithertodiscovered.