Electrostatic and shape complementarity plays an important role in protein–ligand and protein–protein interactions (PPIs). Appropriate molecular volume and reasonable electrostatic potential distribution (EPD) should be helpful for molecular binding and will endow the molecules with more potential in drug development. We have identified an antitumor isoindolinone-containing cyclopeptide (named S-PK6) capable of targeting murine double minute-2 (MDM2) oncoprotein based on Western blotting and isothermal titration calorimetry. In this study, we have explored the influence of the molecular electrostatic potential and volume of cyclopeptides on their docking affinity to MDM2 protein by investigating a series of S-PK6-derived cyclopeptides with different volumes and EPDs. We fortunately found a clear positive correlation between the molecular volumes of cyclopeptides within eight amino acid residues and the target affinity. And, by redistributing the electrostatic potential surface through the introduction of electron-donor or electron-acceptor groups around the potential extremum, the affinity of cyclopeptides to MDM2 protein can be enhanced efficiently, implying a feasible method for structural modification. The research initiates a reconsideration of electrostatic potential and volume in drug design and provides a physicochemical perspective for the development of cyclopeptide drugs.