Structure-Guided Drug Design of 6-Substituted Adenosine Analogues as Potent Inhibitors of Mycobacterium tuberculosis Adenosine Kinase.

Authors:
Qun Dang
Qun Dang
Jilin University
China
Nian E Zhou
Nian E Zhou
SynPhar Laboratories
Edmonton | Canada
Wen Dong
Wen Dong
Sun Yat-sen University
China
Kimberly A Loesch
Kimberly A Loesch
Texas A&M University
College Station | United States
Takao Suzuki
Takao Suzuki
Tokyo Metropolitan Institute of Gerontology
Japan

J Med Chem 2019 May 19;62(9):4483-4499. Epub 2019 Apr 19.

Department of Biochemistry and Biophysics , Texas A&M University , College Station , Texas 77843 , United States.

Mycobacterium tuberculosis adenosine kinase (MtbAdoK) is an essential enzyme of Mtb and forms part of the purine salvage pathway within mycobacteria. Evidence suggests that the purine salvage pathway might play a crucial role in Mtb survival and persistence during its latent phase of infection. In these studies, we adopted a structural approach to the discovery, structure-guided design, and synthesis of a series of adenosine analogues that displayed inhibition constants ranging from 5 to 120 nM against the enzyme. Two of these compounds exhibited low micromolar activity against Mtb with half maximal effective inhibitory concentrations of 1.7 and 4.0 μM. Our selectivity and preliminary pharmacokinetic studies showed that the compounds possess a higher degree of specificity against MtbAdoK when compared with the human counterpart and are well tolerated in rodents, respectively. Finally, crystallographic studies showed the molecular basis of inhibition, potency, and selectivity and revealed the presence of a potentially therapeutically relevant cavity unique to the MtbAdoK homodimer.

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.jmedchem.9b00020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6511943PMC
May 2019

Publication Analysis

Top Keywords

tuberculosis adenosine
8
adenosine analogues
8
salvage pathway
8
adenosine kinase
8
mycobacterium tuberculosis
8
purine salvage
8
activity mtb
4
micromolar activity
4
mtb half
4
low micromolar
4
exhibited low
4
maximal effective
4
μm selectivity
4
selectivity preliminary
4
concentrations μm
4
inhibitory concentrations
4
effective inhibitory
4
half maximal
4
compounds exhibited
4
structure-guided design
4

Similar Publications