Insight into the binding mechanisms of inhibitors of MDM2 are of significance for the development of drugs targeting the p53-MDM2 protein complex. In this work, an MD simulation, MM-GBSA, and SIE methods are combined to study the interaction details of MDM2 with three small nutlins. Structural analyses show that inhibitor binding can weaken the structural flexibility of MDM2. Energy analyses show that the hot spots of the p53-MDM2 interaction can be well-mimicked by two chlorophenyl groups and an ethoxybenzene group. Moreover, an additional strong hot spot (V89) was detected.