【文章名】Lavendamycin Antitumor Agents: Structure-Based Design, Synthesis, and NAD(P)H:Quinone Oxidoreductase 1 (NQO1) Model Validation with Molecular Docking and Biological Studies.
Lavendamycin Antitumor Agents: Structure-Based Design, Synthesis, and NAD(P)H:Quinone Oxidoreductase 1 (NQO1) Model Validation with Molecular Docking and Biological Studies.
作者
Hassani, Mary;Cai, Wen;Koelsch, Katherine H.;Holley, David C.;Rose, Anthony S.;Olang, Fatemeh;Lineswala, Jayana P.;Holloway, William G.;Gerdes, John M.;Behforouz, Mohammad;Beall, Howard D.;
[摘要]：A 1H69 crystal structure-based in silico model of the NAD(P)H:quinone oxidoreductase 1 (NQO1) active site has been developed to facilitate NQO1-directed lavendamycin antitumor agent development. Lavendamycin analogs, e.g. I, were designed as NQO1 substrates utilizing structure-based design criteria. Computational docking studies were performed using the model to predict NQO1 substrate specificity. Designed N-acyllavendamycin esters and amides were synthesized by Pictet-Spengler condensation. Metab. and cytotoxicity studies were performed on the analogs with recombinant human NQO1 and human colon adenocarcinoma cells (NQO1-deficient BE and NQO1-rich BE-NQ). Docking and biol. data were found to be correlated where analogs were categorized as good, poor, poor, poor, and good NQO1 substrates, resp. Our results demonstrated that the ligand design criteria were valid, resulting in the discovery of two good NQO1 substrates. The obsd. consistency between the docking and biol. data suggests that the model possesses practical predictive power.
