Identification of novel inhibitors of p53–MDM2 interaction facilitated by pharmacophore-based virtual screening combining molecular docking strategy

Abstract

3D pharmacophore models for inhibitors of p53–MDM2 interaction were developed. The pharmacophore-based virtual screening of an in-house compound database combined with docking studies led to the identification of compound MCL0527 as a novel lead (MDM2 binding IC₅₀ = 4.23 μM). Initial structure optimization yielded some derivatives with improved p53–MDM2 binding inhibitory activities. Furthermore, all target compounds showed potent anti-proliferative effect against human tumor cell lines with a generally selective profile on wild-type p53 cell lines.