title: Identification of New Structural Fragments for the Design of Lactate Dehydrogenase A Inhibitors.
abstract: Human lactate dehydrogenase A plays an important role in the glucose metabolism of tumor cells and constitutes an attractive target for chemotherapy. Molecular fragments able to bind in the active site of this enzyme and form hydrogen bonds with the Arg168 guanidinium group, as well as additional interactions with the loop 96-111 in the closed conformation, have been identified by virtual screening of sulfonates and experimental testing of their inhibitory effect. The sulfo group can occupy a similar position as the carboxyl group of the substrate and its structural analogs, whereas the benzothiazole group attached via a linker can be located in the coenzyme (NADH) binding site. Thus, the value of merging individual structural elements of the inhibitor by a linker was demonstrated and ways of further structural modification for the design of more effective inhibitors of lactate dehydrogenase A were established.
authors: Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, Lenin Hills 1 , bldg. 40, Moscow, 119991, Russia.
authors: D K
authors: DK
authors: Nilov
authors: Faculty of Fundamental Medicine, Lomonosov Moscow State University, Lomonosov prospect 31- 5 , Moscow, 119192, Russia.
authors: A V
authors: AV
authors: Kulikov
authors: Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Lenin Hills 1, bldg. 73, Moscow, 119991, Russia.
authors: E A
authors: EA
authors: Prokhorova
authors: Belozersky Institute of Physicochemical Biology, Lomonosov Moscow State University, Lenin Hills 1 , bldg. 40, Moscow, 119991, Russia ; Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, Lenin Hills 1, bldg. 73, Moscow, 119991, Russia.
authors: V K
authors: VK
authors: Švedas
keywords: Lactate dehydrogenase; docking; inhibitor; molecular modeling; sulfo group; sulfonates