Abstract:The conformational relationship between the structure and acute toxicity of 1，4-dihydropyridines（1，4-DHPs）was investigated and the possible mechanisms causing changes in acute toxicity were analyzed using 3-dimensional-quantitative structure-activity relationship（3D-QSAR）models.The 3D structures and 50% lethal dose（LD50）values of 11 1，4-DHPs were processed accordingly，and the 3D-QSAR models were constructed using comparative molecular force field analysis（CoMFA）and comparative molecular similarity index analysis（CoMSIA），followed by internal and external validation of the 3D-QSAR models and application domain.The cross-validation coefficients（q2）for the CoMFA and CoMSIA models were found to be 0.509 and 0.521，respectively，and the non-cross-validation coefficients（R2）were 0.988 and 0.989，respectively.The predictions of acute toxicity were consistent with experimental results.Changes in the acute toxicity changes of 1，4-DHPs were mainly driven by steric，electrostatic，hydrophobic，and hydrogen bond acceptor fields，as shown by the application of four molecular fields to the pyridine 3 substituent of 1，4-DHPs，steric and hydrogen bond acceptor fields to the pyridine 5 substituent，and steric，electrostatic and hydrophobic fields to the benzene ring substituent；all of these substituents resulted in changes in the acute toxicity changes of 1，4-DHPs.In conclusion，a 3D-QSAR model with high predictive power for acute toxicity of 1，4-DHPs was developed in this study.The model is expected to provide not only technical support for predicting the acute toxicity of 1，4-DHPs but also ideas for the design of new 1，4-DHPs-based calcium channel blockers.