Medicinal Chemistry & Targeted Drug Delivery

MDM2 (Mouse double minute 2 homolog) is known as a protein which is a significant negative regulator of p53. MDM2 is also considered to be E3 ubiquitin-protein ligase recognizing the N-terminal TAD (trans activation domain). Thus, MDM2-p53 interactions is proposed to be a promising therapeutic strategy for tumors. Previously, we reported a part of the FMO (Fragment Molecular Orbital) calculation results of MDM2 and its inhibitors at Chem-Bio Informatics Society (CBI). However, we could not obtain sufficient correlation between calculated and observed activities of the inhibitors. In this study, we added some FMO results and tried to obtain better correlation using data mining methods, such as PLS. First, we selected significant 53 amino acids from 85 ones for interactions between MDM2 and inhibitors considering the IFIE values. Then we obtained two latent variables as a result of PLS and cross validations. Resulted scatter plot between observed and calculated pIC50 of MDM2 is shown in Figure 1. we could obtain better correlation coefficient, R2=0.879. We are now calculating PIEDA of the complexes.