Identification of new inhibitors of Mdm2–p53 interaction via pharmacophore and structure-based virtual screening

Figures & data

Figure 1 Various families of Mdm2 inhibitors shown along with their interaction fingerprints.

Notes: c indicates contact interaction, a indicates hydrogen bond acceptor, i indicates ionic interaction.

Figure 2 The Mdm2 inhibitor 3D pharmacophore, used to filter out the initial drug-like library, is shown inside the pocket of Mdm2 protein (shown as surface).

Abbreviations: Aro, aromatic; Hyd, hydrophobic.

Figure 3 The drug design approach employed in this study to discover new Mdm2–p53 inhibitors.

Abbreviations: GLIDE, grid-based ligand docking with energetics; SP, standard precision; XP, extra precision.

Table 1 Inhibition activity of the tested top docked compounds along with Nutlin 3a²⁰ against the Mdm2–p53 interaction using ELISA

Compound	2D structure	TimTec code	Docking score	IC50 (±SE) μM
S01		ST054022	−7.16	0.54±0.037
S02		ST094416	−7.18	0.42±0.036
S05		ST45218648	−7.46	0.87±0.160
S25		ST005927	−7.63	0.66±0.083
S27		ST50128825	−7.53	0.73±0.104
Nutlin 3a		–	−7.472	0.30±0.045

Abbreviation: IC₅₀, inhibitory concentration of 50% of the sample.

Figure 4 The docked ligand pose of S01 with the p53 binding site of the Mdm2 protein.

Note: Hydrogen bonding is shown in blue and π-hydrogen is shown in green.
Abbreviations: Aro, aromatic; Hyd, hydrophobic.

Figure 5 The docked ligand pose of S02 with the p53 binding site of the Mdm2 protein.

Note: Hydrogen bonding is shown in blue and π-hydrogen is shown in green.
Abbreviations: Aro, aromatic; Hyd, hydrophobic.

Figure 6 The docked ligand pose of S05 with the p53 binding site of the Mdm2 protein.

Note: Hydrogen bonding is shown in blue and π-hydrogen is shown in green.
Abbreviations: Aro, aromatic; Hyd, hydrophobic.

Figure 7 Protein–ligand interaction diagram of S25 (A) and S27 (B).

Figure 8 The IC₅₀ values (µM) of the examined inhibitors on three human breast cancer cell lines.

Note: Values are expressed as mean±SD of three independent experiments (n=6).
Abbreviation: IC₅₀, inhibitory concentration of 50% of the sample.

Table 2 Similarity scores of the newly discovered compounds compared to previously known inhibitors

Hits	2D structure	Previously reported inhibitor (PDB source)	2D structure	Overlapping
S01		3JZK		73%
S02		4OQ3		53%
S05		4JV7		59%
S25		4DIJ		44%
S27		4JV9		58%

Abbreviation: PDB, protein data bank.

VassilevLTVuBTGravesBIn vivo activation of the p53 pathway by small-molecule antagonists of MDM2Science2004303565984484814704432

 PubMed Web of Science ®Google Scholar