Vasoactive intestinal polypeptide (VIP) is an intrinsic 28-amino acid peptide, involved in a wide range of physiologic effects, and therefore considered as a promising drug candidate for the treatment of several diseases. But the clinical application of VIP has been limited for the easy in vivo digestion. Various researches aiming to prolong the VIP half-life, by modifying the VIP structure, have been reported. The first thing to be considered after structural modification is to know it is a VPAC agonist or antagonist. To analyze the structure-activity relationships of VIP derivatives and build classifiers to distinguish newly designed VIPs, here in this work, we collected 46 samples and two classifiers were established respectively for VPAC1 and VPAC2 receptors. The built classifiers are robust and predictive with high sensitivity, specificity and concordance for the prediction set. By analyzing the meanings of the used variables, we found that the electrostatic properties of VIP derivatives are vital in their interactions with VPAC receptors. Finally, these two classifiers were used to predict the bioactivities of novel VIPs, without experimental activities, which were suggested for experimental research groups to test their bioactivities and the possible practical applications in future.