title: Structural basis for inhibition of mycobacterial and human adenosine kinase by 7-substituted 7-(Het)aryl-7-deazaadenine ribonucleosides.
abstract: Adenosine kinase (ADK) from Mycobacterium tuberculosis (Mtb) was selected as a target for design of antimycobacterial nucleosides. Screening of 7-(het)aryl-7-deazaadenine ribonucleosides with Mtb and human (h) ADKs and testing with wild-type and drug-resistant Mtb strains identified specific inhibitors of Mtb ADK with micromolar antimycobacterial activity and low cytotoxicity. X-ray structures of complexes of Mtb and hADKs with 7-ethynyl-7-deazaadenosine showed differences in inhibitor interactions in the adenosine binding sites. 1D (1)H STD NMR experiments revealed that these inhibitors are readily accommodated into the ATP and adenosine binding sites of Mtb ADK, whereas they bind preferentially into the adenosine site of hADK. Occupation of the Mtb ADK ATP site with inhibitors and formation of catalytically less competent semiopen conformation of MtbADK after inhibitor binding in the adenosine site explain the lack of phosphorylation of 7-substituted-7-deazaadenosines. Semiempirical quantum mechanical analysis confirmed different affinity of nucleosides for the Mtb ADK adenosine and ATP sites.
authors.affiliation: Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic , Flemingovo nam. 2, 16610 Prague 6, Czech Republic.
authors.forename: Jan
authors.initials: J
authors.lastname: Snášel
authors.forename: Petr
authors.initials: P
authors.lastname: Nauš
authors.forename: Jiří
authors.initials: J
authors.lastname: Dostál
authors.forename: Aleš
authors.initials: A
authors.lastname: Hnízda
authors.forename: Jindřich
authors.initials: J
authors.lastname: Fanfrlík
authors.forename: Jiří
authors.initials: J
authors.lastname: Brynda
authors.forename: Aurelie
authors.initials: A
authors.lastname: Bourderioux
authors.forename: Michal
authors.initials: M
authors.lastname: Dušek
authors.forename: Hana
authors.initials: H
authors.lastname: Dvořáková
authors.forename: Jiřina
authors.initials: J
authors.lastname: Stolaříková
authors.forename: Helena
authors.initials: H
authors.lastname: Zábranská
authors.forename: Radek
authors.initials: R
authors.lastname: Pohl
authors.forename: Petr
authors.initials: P
authors.lastname: Konečný
authors.forename: Petr
authors.initials: P
authors.lastname: Džubák
authors.forename: Ivan
authors.initials: I
authors.lastname: Votruba
authors.forename: Marián
authors.initials: M
authors.lastname: Hajdúch
authors.forename: Pavlína
authors.initials: P
authors.lastname: Rezáčová
authors.forename: Václav
authors.initials: V
authors.lastname: Veverka
authors.forename: Michal
authors.initials: M
authors.lastname: Hocek
authors.forename: Iva
authors.initials: I
authors.lastname: Pichová
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000737:chemistry; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000995:Antitubercular Agents / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D004353:Drug Evaluation, Preclinical; D006801:Humans; D008826:Microbial Sensitivity Tests; D009169:Mycobacterium tuberculosis / Q000187:drug effects* / Q000201:enzymology*; D019906:Nuclear Magnetic Resonance, Biomolecular; D011487:Protein Conformation; D012263:Ribonucleosides / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D000995:Antitubercular Agents; D012263:Ribonucleosides; C043837:7-deazaadenine; D000255:Adenosine Triphosphate; D000248:Adenosine Kinase; D000225:Adenine