CoMFA analysis of tgDHFR and rlDHFR based on antifolates with 6-5 fused ring system using the all-orientation search (AOS) routine and a modified cross-validated r2-guided region selection (q2-GRS) routine and its initial application

Aleem Gangjee, Xin Lin, Lisa R. Biondo, Sherry F. Queener

Research output: Contribution to journalArticle

6 Scopus citations


We report the development of CoMFA analysis models that correlate the 3D chemical structures of 80 compounds with 6-5 fused ring system synthesized in our laboratory and their inhibitory potencies against tgDHFR and rlDHFR. In addition to conventional CoMFA analysis, we used two routines available in the literature aimed at the optimization of CoMFA: all-orientation search (AOS) and cross-validated r2-guided region selection (q2-GRS) to further optimize the models. During this process, we identified a problem associated with q2-GRS routine and modified using two strategies. Thus, for the inhibitory activity against each enzyme (tgDHFR and rlDHFR), five CoMFA models were developed using the conventional CoMFA, AOS optimized CoMFA, the original q2-GRS optimized CoMFA and the modified q2-GRS optimized CoMFA using the first and the second strategy. In this study, we demonstrate that the modified q2-GRS routines are superior to the original routine. On the basis of the steric contour maps of the models, we designed four new compounds in the 2,4-diamino-5-methyl-6-phenylsulfanyl-substituted pyrrolo[2,3-d]pyrimidine series. As predicted, the new compounds were potent and selective inhibitors of tgDHFR. One of them, 2,4-diamino-5-methyl-6-(2′,6′-dimethylphenylthio)pyrrolo[2,3-d]pyrimidine, is the first 6-5 fused ring system compound with nanomolar tgDHFR inhibitory activity. The HCl salt of this compound was also prepared to increase solubility. Both forms of the drug were tested in vivo in a Toxoplasma gondii infection mouse model. The results indicate that both forms were active with the HCl salt significantly more potent than the free base.

Original languageEnglish (US)
Pages (from-to)1684-1701
Number of pages18
JournalBioorganic and Medicinal Chemistry
Issue number4
StatePublished - Feb 15 2010



  • Antifolates
  • CoMFA analysis
  • Dihydrofolate reductase
  • Selective inhibitors

ASJC Scopus subject areas

  • Pharmaceutical Science
  • Drug Discovery
  • Organic Chemistry
  • Molecular Medicine
  • Molecular Biology
  • Clinical Biochemistry
  • Biochemistry

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