Identification of High Affinity Non-Peptidic Small Molecule Inhibitors of MDM2-p53 Interactions through Structure-Based Virtual Screening Strategies

Abstract

Background: 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.

Identification of High-Affinity Small Molecule Targeting IDH2 for the Clinical Treatment of Acute Myeloid Leukemia

“…LLC, New York, NY) (Babitha et al, 2015;Bandaru et al, 2017a;Basak et al, 2016a, Dunna et al, 2015a. Eventually, in this procedure of preparation, the protein was added with disulfide bonds, missing side chains were filled, water molecules were removed beyond 5 Å from hetero groups, and was saved in the SDF format for further docking studies (Dunna et al, 2015b;Divya et al, 2019;Bandaru et al, 2015a;Kelotra et al, 2014a;Basak et al, 2016b).…”

Design of novel JAK3 Inhibitors towards Rheumatoid Arthritis using molecular docking analysis

“…Similarity search was carried out against this best-established compound to get a superior compound possessing a larger binding affinity to the 3D crystal structure, other than any previously established drugs [53-57]. This similarity searching was carried out against PubChem database developed by NIH, one of the public chemical repositories, which contain structures of 93 million chemical compounds [58-61]. The filtration property parameter set by component rule of Lipinski's rule of five was set at threshold >=95.…”

Identification of Potent VEGF Inhibitors for the Clinical Treatment of Glioblastoma, A Virtual Screening Approach

“…Further preparation of ligand was preceded by taking the 3D structure of all those compound embedded in LegPrep module, an application of Schrodinger suite (Schrodinger. LLC, New York, NY) and were optimized through OPLS 2005 force field algorithm (Bandaru et al, 2015a;Bandaru S et al, 2015b;Babitha et al, 2015;Chandrakar et al, 2013;Divya Jain et al, 2019;Dunna et al, 2015a;Gudala, et al, 2015;Majhi et al, 2018). The prepared ligands were saved in a single SDF file for further docking studies (Bandaru et al, 2016;Basak et al, 2016a;Dunna et al, 2015b;Mendonça-Junior et al, 2019;Nasr et al, 2015).…”