title: Comparative molecular field analysis and comparative molecular similarity indices analysis of human thymidine kinase 1 substrates.
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 r(2) (q(2))=0.651, non-cross-validated r(2)=0.980, standard error of estimate (s)=0.207, F=129.3. For the optimal CoMSIA model the following values were found: q(2)=0.619, r(2)=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.
authors.affiliation: Division of Medicinal Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Achintya K
authors.initials: AK
authors.lastname: Bandyopadhyaya
authors.forename: Jayaseharan
authors.initials: J
authors.lastname: Johnsamuel
authors.forename: Ashraf S
authors.initials: AS
authors.lastname: Al-Madhoun
authors.forename: Staffan
authors.initials: S
authors.lastname: Eriksson
authors.forename: Werner
authors.initials: W
authors.lastname: Tjarks
mesh_terms: D006801:Humans; D008958:Models, Molecular; D010766:Phosphorylation; D021281:Quantitative Structure-Activity Relationship; D013379:Substrate Specificity; D013937:Thymidine Kinase / Q000378:metabolism*
chemical_list: D013937:Thymidine Kinase; C092717:thymidine kinase 1