Comparative molecular field analysis and comparative molecular similarity indices analysis of human thymidine kinase 1 substrates

Achintya K. Bandyopadhyaya, Jayaseharan Johnsamuel, Ashraf Al Madhoun, Staffan Eriksson, Werner Tjarks

Research output: Contribution to journalArticlepeer-review

20 Citations (Scopus)

Abstract

Thymidine kinase 1 (TK1) is a key target for antiviral and anticancer chemotherapy. Three-dimensional quantitative structure-activity relationship (3D-QSAR) using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) techniques was applied to analyze the phosphorylation capacity of a series of 31 TK1 substrates. The optimal predictive CoMFA model with 26 molecules provided the following values: cross-validated r2 (q2) = 0.651, non-cross-validated r2 = 0.980, standard error of estimate (s) = 0.207, F = 129.3. For the optimal CoMSIA model the following values were found: q2 = 0.619, r2 = 0.994, s = 0.104, F = 372.2. The CoMSIA model includes steric, electrostatic, and hydrogen bond donor fields. The predictive capacity of both models was successfully validated by calculating known phosphorylation rates of five TK1 substrates that were not included in the training set. Contour maps obtained from CoMFA and CoMSIA models correlated with the experimentally developed SAR.

Original languageEnglish
Pages (from-to)1681-1689
Number of pages9
JournalBioorganic and Medicinal Chemistry
Volume13
Issue number5
DOIs
Publication statusPublished - 1 Mar 2005

Keywords

  • 3D-QSAR
  • CoMFA
  • CoMSIA
  • Thymidine kinase 1 (TK1)
  • TK1 substrates

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