QSAR analysis of 2,4-diaminopyrido[2,3-d]pyrimidines and 2,4-diaminopyrrolo[2,3-d]pyrimidines as dihydrofolate reductase inhibitors.

Dihydrofolate reductase (DHFR) plays a ubiquitous role in the biosynthesis of DNA, RNA and essential amino acid methionine, and exhibits potential application in the treatment and prophylaxis of AIDS-associated opportunistic microbial infections. In this study, a series of DHFR analogs of 2,4-diaminopyrido[2,3-d]pyrimidines and 2,4-diaminopyrrolo[2,3-d]pyrimidines were subjected to quantitative structure-activity relationship (QSAR) analysis. The results showed that the electronic properties, energy of lowest unoccupied molecular orbital (LUMO) and Z-component of dipole moment (DPL3) of the molecule could be explored to design the potent DHFR inhibitors. LUMO is indicative of pi-bonding interaction of species crucial for the electrophilicity of the molecules. This suggests that molecules are able to interact with electron-rich area at the receptor site. DPL3 is related to the molecular charge distribution in Z-component. These electronic parameters can be altered through the incorporation of electronegative groups. The QSAR study provides important structural insights for designing the potent DHFR inhibitors.