Prediction of residues involved in inhibitor specificity in the dihydrofolate reductase family

N. M. Goodey, K. G. Herbert, S. M. Hall, K. C. Bagley

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Dihydrofolate reductase (DHFR) is of significant recent interest as a target for drugs against parasitic and opportunistic infections. Understanding factors which influence DHFR homolog inhibitor specificity is critical for the design of compounds that selectively target DHFRs from pathogenic organisms over the human homolog. This paper presents a novel approach for predicting residues involved in ligand discrimination in a protein family using DHFR as a model system. In this approach, the relationship between inhibitor specificity and amino acid composition for sets of protein homolog pairs is examined. Similar inhibitor specificity profiles correlate with increased sequence homology at specific alignment positions. Residue positions that exhibit the strongest correlations are predicted as specificity determinants. Correlation analysis requires a quantitative measure of similarity in inhibitor specificity (S lig) for a pair of homologs. To this end, a method of calculating Slig values using KI values for the two homologs against a set of inhibitors as input was developed. Correlation analysis of S lig values to amino acid sequence similarity scores - obtained via multiple sequence alignments - was performed for individual residue alignment positions and sets of residues on 13 DHFRs. Eighteen alignment positions were identified with a strong correlation of Slig to sequence similarity. Of these, three lie in the active site; four are located proximal to the active site, four are clustered together in the adenosine binding domain and five on the βFβG loop. The validity of the method is supported by agreement between experimental findings and current predictions involving active site residues.

Original languageEnglish
Pages (from-to)1870-1879
Number of pages10
JournalBiochimica et Biophysica Acta - Proteins and Proteomics
Issue number12
StatePublished - Dec 2011


  • Allosteric interaction
  • Dihydrofolate reductase
  • Drug-target interaction
  • Inhibitor specificity
  • Specificity determinant
  • Target prediction


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