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Title: Increasing the structural coverage of tuberculosis drug targets

High-resolution three-dimensional structures of essential Mycobacterium tuberculosis (Mtb) proteins provide templates for TB drug design, but are available for only a small fraction of the Mtb proteome. Here we evaluate an intra-genus “homolog-rescue” strategy to increase the structural information available for TB drug discovery by using mycobacterial homologs with conserved active sites. We found that of 179 potential TB drug targets selected for x-ray structure determination, only 16 yielded a crystal structure. By adding 1675 homologs from nine other mycobacterial species to the pipeline, structures representing an additional 52 otherwise intractable targets were solved. To determine whether these homolog structures would be useful surrogates in TB drug design, we compared the active sites of 106 pairs of Mtb and non-TB mycobacterial (NTM) enzyme homologs with experimentally determined structures, using three metrics of active site similarity, including superposition of continuous pharmacophoric property distributions. Pair-wise structural comparisons revealed that 19/22 pairs with >55% overall sequence identity had active site Cα RMSD <1 Å, >85% side chain identity, and ≥80% PSAPF (similarity based on pharmacophoric properties) indicating highly conserved active site shape and chemistry. Applying these results to the 52 NTM structures described above, 41 shared >55% sequence identity with the Mtb target,more » thus increasing the effective structural coverage of the 179 Mtb targets over three-fold (from 9% to 32%). The utility of these structures in TB drug design can be tested by designing inhibitors using the homolog structure and assaying the cognate Mtb enzyme; a promising test case, Mtb cytidylate kinase, is described. The homolog-rescue strategy evaluated here for TB is also generalizable to drug targets for other diseases.« less
Authors:
 [1] ;  [1] ;  [2] ;  [2] ;  [2] ;  [2] ;  [2] ;  [2] ;  [2] ;  [3] ;  [3] ;  [3] ;  [1] ;  [4] ;  [5] ;  [5] ;  [5] ;  [5] ;  [5] ;  [1] more »;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [1] ;  [2] ;  [6] ;  [1] ;  [7] ;  [2] ;  [8] ;  [9] « less
  1. Seattle Structural Genomics Center for Infectious Disease (United States); Seattle Biomedical Research Inst., Seattle, WA (United States)
  2. Seattle Structural Genomics Center for Infectious Disease (United States); Beryllium, Bainbridge Island, WA (United States)
  3. Beryllium, Bainbridge Island, WA (United States)
  4. Seattle Structural Genomics Center for Infectious Disease (United States); Beryllium, Bainbridge Island, WA (United States); EMD Serono Research & Development Inst., Inc., Billerica, MA (United States)
  5. Seattle Structural Genomics Center for Infectious Disease (United States); Univ. of Washington, Seattle, WA (United States). Dept. of Medicine
  6. Seattle Structural Genomics Center for Infectious Disease (United States); Pacific Northwest National Lab. (PNNL), Richland, WA (United States). Biological Sciences Division
  7. Seattle Structural Genomics Center for Infectious Disease (United States); Beryllium, Bainbridge Island, WA (United States); Univ. of Washington, Seattle, WA (United States). Inst. for Protein Design
  8. Seattle Structural Genomics Center for Infectious Disease (United States); Univ. of Washington, Seattle, WA (United States). Dept. of Medicine; Univ. of Washington, Seattle, WA (United States). Dept. of Global Health; Univ. of Washington, Seattle, WA (United States). Dept. of Microbiology
  9. Seattle Structural Genomics Center for Infectious Disease (United States); Seattle Biomedical Research Inst., Seattle, WA (United States); Univ. of Washington, Seattle, WA (United States). Dept. of Global Health; Univ. of Washington, Seattle, WA (United States). Dept. of Biomedical Informatics and Medical Education
Publication Date:
OSTI Identifier:
1182307
Grant/Contract Number:
HHSN272200700057C; HHSN272201200025C
Type:
Accepted Manuscript
Journal Name:
Tuberculosis
Additional Journal Information:
Journal Volume: 95; Journal Issue: 2; Journal ID: ISSN 1472-9792
Publisher:
Elsevier
Research Org:
Pacific Northwest National Laboratory (PNNL), Richland, WA (United States)
Sponsoring Org:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23); National Inst. of Health (NIH)
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES Drug discovery; homolog-rescue; structural genomics; enzyme active site