P. carinii dihydrofolate reductase (PcDHFR) inhibitors are used for the treatment of P.
carinii pneumonia (PCP) in humans with acquired immunodeficiency syndrome (AIDS). Translocation
comparative molecular field vector analysis (Topomer CoMFA) 3D-QSAR and molecular docking
were applied for a series of pyrimidine derivatives. 64 Pyrimidine derivatives were analyzed and
the relationship between the structures and bioactivities was explored. Topomer CoMFA was used to
build 3D-QSAR model, the results show that cross-validation q2 = 0.721, SDCV = 0.52, the non-crossvalidated
r2 = 0.922, SD = 0.28, and the correlation coefficient of external validation Q2
ext = 0.934,
this indicated that model generated form Topomer CoMFA was reasonable, and had good prediction
ability. The mechanism of action of drug was studied by molecular docking. It showed that the
pyrimidine compounds and GLU32, ILE123, LYS37 sites of PcDHFR have interactions. These results
have provided an insight for the design of new potent inhibitors of PcDHFR.