Comparative molecular field analysis and comparative molecular similarity indices analysis of boron-containing human thymidine kinase 1 substrates.
Three-dimensional quantitative structure-activity relationship (3D-QSAR) using CoMFA and CoMSIA techniques was applied to evaluate 56 pyrimidine nucleosides as substrates of human thymidine kinase 1 (hTK1), 27 of them containing a carborane substituent either at the 3-, 5-, or 3'-position of the 2'-deoxyuridine scaffold. This is the first report describing 3D-QSAR studies of compounds containing boron atoms. Both CoMFA and CoMSIA models were derived from a training set of 47 molecules and the predictive capacity of the CoMSIA model was successfully validated by accurately calculating known phosphorylation rates of both boronated and non-boron hTK1 substrates that were not included in the training set. The optimal CoMSIA model provided the following values: q(2) 0.622, r(2) 0.983, s 0.165, and F 187.5. Contour maps obtained from the CoMSIA model were in agreement with the experimentally determined biological data.
Bandyopadhyaya
Achintya K
AK
Division of Medicinal Chemistry and Pharmacognosy, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA. bandyopadhyaya.1@osu.edu
Tiwari
Rohit
R
Tjarks
Werner
W
D001895:Boron / Q000737:chemistry*; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D021281:Quantitative Structure-Activity Relationship; D055672:Static Electricity; D013379:Substrate Specificity; D013937:Thymidine Kinase / Q000737:chemistry*
D013937:Thymidine Kinase; C092717:thymidine kinase 1; D001895:Boron