TY - JOUR
T1 - Comparative molecular field analysis and comparative molecular similarity indices analysis of human thymidine kinase 1 substrates
AU - Bandyopadhyaya, Achintya K.
AU - Johnsamuel, Jayaseharan
AU - Al Madhoun, Ashraf
AU - Eriksson, Staffan
AU - Tjarks, Werner
PY - 2005/3/1
Y1 - 2005/3/1
N2 - 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.
AB - 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.
KW - 3D-QSAR
KW - CoMFA
KW - CoMSIA
KW - Thymidine kinase 1 (TK1)
KW - TK1 substrates
UR - http://www.scopus.com/inward/record.url?scp=13444267623&partnerID=8YFLogxK
U2 - 10.1016/j.bmc.2004.12.008
DO - 10.1016/j.bmc.2004.12.008
M3 - Article
C2 - 15698786
AN - SCOPUS:13444267623
VL - 13
SP - 1681
EP - 1689
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
SN - 0968-0896
IS - 5
ER -