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.
Molecular Modelling Study Group, CADD Laboratory, Department of Pharmacy, S.G.S.I.T.S., 23 Park Road, Indore 452 003, M.P., India.
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P
Jain
L K
LK
Soni
A K
AK
Gupta
S G
SG
Kashkedikar
D000818:Animals; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects; D015394:Molecular Structure; D009162:Mycobacterium avium / Q000187:drug effects; D045363:Pneumocystis carinii / Q000187:drug effects; D011743:Pyrimidines / Q000737:chemistry*; D021281:Quantitative Structure-Activity Relationship; D051381:Rats; D013762:Tetrahydrofolate Dehydrogenase / Q000737:chemistry* / Q000378:metabolism; D014122:Toxoplasma / Q000187:drug effects
D004791:Enzyme Inhibitors; D011743:Pyrimidines; D013762:Tetrahydrofolate Dehydrogenase