Abstract B45: Molecular modeling approach for exploring the MDM2 active site for the discovery of new P53-MDM2 inhibitors

Abstract

MDM2 is a protein that regulates the action of tumor suppressor protein P53. Inhibiting the interaction between the two proteins is widely considered in anti-cancer drug discovery approach. Targeting p53-bindig site on the MDM2 protein can be useful for the development of new anticancer agents. Several drugs with selective activity have been introduced to the market and are used for treatment of several types of cancers. In this study we explored the inhibition of MDM2 activity through studying 32 crystal structures of MDM2-ligand complexes downloaded from protein data bank (PDB). MDM2 protein structures were analyzed using protein-ligand interaction fingerprint to determine key residues for ligand binding. A 3D pharmacophore set was created and validated with a set of features that include aromatic and hydrophobic properties. Furthermore libraries of potential small lead-like ligands were screened on the pharmacophore. Ligands which pose three pharmacophoric features were carried to the next step where receptor-based virtual screening was performed using GLIDE docking software. The top 10% obtained from this screening were then redocked into the MDM2 binding site using more extensive search and scoring technique (GLIDE_XP) in order to enhance screening accuracy. The resultant top list was visually examined and compounds with best binding mode were selected for experimental testing. This virtual technique for discovering new lead-like MDM2 inhibitors will take into consideration several features that current inhibitors may lack such as solubility and bioavailability. Citation Format: Noor Atatreh, Ramez A. Mansour, Mohammad A. Ghattas. Molecular modeling approach for exploring the MDM2 active site for the discovery of new P53-MDM2 inhibitors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B45.