A lack of specificity is restricting the further application of conotoxin from Conus bullatus (BuIA). In this study, an analogue library of BuIA was established and virtual screening was used, which identified high α7 nicotinic acetylcholine receptor (nAChR)-selectivity analogues. The results showed that the analogues maintained their capacity for calcium regulation. Also,the hot-plate model and paclitaxel-induced peripheral neuropathy model indicated that, when compared with natural BuIA, the analgesia activities of the analogues in different models were maintained. The results of adverse effects and toxicity showed that the safety and toxicity of the analogues were significantly better than BuIA. The analogues of BuIA with an appropriate and rational mutation showed high selectivity and maintained the regulation of Ca2+ capacity in neurons and activities of analgesia, whereas the analogues demonstrated that the adverse effects of natural α-conotoxins could be reduced.