PMID- 22646985
OWN - NLM
STAT- PubMed-not-MEDLINE
DCOM- 20121002
LR  - 20140731
IS  - 1746-045X (Electronic)
IS  - 1746-0441 (Linking)
VI  - 6
IP  - 11
DP  - 2011 Nov
TI  - Current possibilities and unresolved issues of drug target validation in 
      Mycobacterium tuberculosis.
PG  - 1171-86
LID - 10.1517/17460441.2011.626763 [doi]
AB  - INTRODUCTION: Target driven drug discovery is a long and arduous task requiring a 
      huge investment of time, energy and resources. Therefore, it is very important to 
      select targets which provide the maximum chance of obtaining inhibitors that will 
      be efficacious in animal models and finally in tuberculosis (TB) patients. AREAS 
      COVERED: The article discusses the necessity for new targets in Mycobacterium 
      tuberculosis (Mtb) drug discovery and how the functional redundancy of putative 
      targets in Mtb adds a new dimension to the complexity of validation. The article 
      also reviews survival kinetics using conditional knockout (KO) or knockdown (KD) 
      strains and discusses how this has provided crucial information on target 
      vulnerability. Furthermore, the article also comments on how the chemical 
      validation of new targets using specific inhibitors has greatly supplemented the 
      genetic validation efforts. EXPERT OPINION: Because of complexity of pathogenesis 
      of TB, the putative drug targets need to be validated under multiple 
      physiological conditions. Target protein depletion can mimic chemical inhibition 
      and, therefore, will be a valuable tool in predicting the vulnerability of a 
      target. Conditional KO or KD makes it possible to study the phenotypes of Mtb 
      strains under a variety of physiological states. The phenotype of these strains 
      should also be tested in animal models which mimic human TB more closely. 
      Finally, inhibitors with confirmed mode of action can be important tools for 
      validating Mtb drug targets.
FAU - Sharma, Umender
AU  - Sharma U
AD  - AstraZeneca R & D, Bioscience, "Avishkar", Bellary road, Hebbal, Bangalore, 
      560024 , India umender.sharma@astrazeneca.com.
LA  - eng
PT  - Journal Article
DEP - 20111025
PL  - England
TA  - Expert Opin Drug Discov
JT  - Expert opinion on drug discovery
JID - 101295755
EDAT- 2012/06/01 06:00
MHDA- 2012/06/01 06:01
CRDT- 2012/06/01 06:00
PHST- 2012/06/01 06:00 [entrez]
PHST- 2012/06/01 06:00 [pubmed]
PHST- 2012/06/01 06:01 [medline]
AID - 10.1517/17460441.2011.626763 [doi]
PST - ppublish
SO  - Expert Opin Drug Discov. 2011 Nov;6(11):1171-86. doi: 
      10.1517/17460441.2011.626763. Epub 2011 Oct 25.