Molecular modelling studies of new potential human DNA polymerase α inhibitors.
The human polymerase α (pol α) is a promising target for the therapy of cancer e.g. of the skin. The authors recently built a homology model of the active site of human DNA pol α. This 3D model was now used for molecular modelling studies with eight novel analogues of 2-butylanilino-dATP, which is a highly selective nucleoside inhibitor of mammalian pol α. Our results suggest that a higher hydrophobicity of a carbohydrate side chain (pointing into a spacious hydrophobic cavity) may enhance the strength of the interaction with the target protein. Moreover, acyclic acyclovir-like derivatives outperformed those with a sugar-moiety, indicating that structural flexibility and higher conformational adaptability has a positive effect on the receptor affinity. Cytotoxicity tests confirmed our theoretical findings. Besides, one of our most promising compounds in the molecular modelling studies revealed high selectivity for the SCC-25 cell line derived from squamous cell carcinoma in man.
Zdrazil
Barbara
B
Department of Pharmaceutical/Medicinal Chemistry, Heinrich-Heine-Universität Düsseldorf, Universitätsstraße 1, 40225 Düsseldorf, Germany. barbara.zdrazil@univie.ac.at
Schwanke
Anja
A
Schmitz
Birte
B
Schäfer-Korting
Monika
M
Höltje
Hans-Dieter
HD
D020134:Catalytic Domain; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D006801:Humans; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D013329:Structure-Activity Relationship
D004256:DNA Polymerase I