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OJBTM
Online Journal of
Bioinformatics ©
Volume 14 (3): 282-292, 2013
Virtual dihydroxy
acid dehydratase inhibitors for
tuberculosis
Jena
L1,2, Kumar S1*
1Bioinformatics Centre &
Biochemistry,
Mahatma Gandhi Institute of Medical Sciences,
Sevagram, Maharashtra and 2Department
of
Bioinformatics, Shri JJT
University, Jhunjhunu, Rajasthan,
India
Jena
L, Kumar S., Virtual dihydroxy
acid dehydratase
inhibitors for tuberculosis, Onl
J Bioinform., 14 (3): 282-292,
2013. Dihydroxy
acid dehydratase (DHAD) encoded
by the gene Rv0189c is essential
for biosynthesis
of BCAA and pantothenate
(coenzyme A) in Mycobacterium
tuberculosis (MTB). A 3D
model of DHAD was built using Phyre
2 server followed
by structural refinement and energy minimization by YASARA
Energy Minimization
server. The refined model reliability was assessed through Procheck,
ProSA and ProQ.
A dataset
of 135 Drug like compounds were retrieved from ZINC database
based on the
properties similar to the DHAD natural substrate 2,3-dihydroxy-3-methylbutanoate.
Molecular docking program Auto Dock Vina
in PyRx 0.8 was applied to
identify two drug-like compounds,
ZINC40397312 (1-(1H-1,2,3,4-tetrazol-5-yl)cyclobutan-1-amine)
and
ZINC00330490 (6-hydroxy-2-(methylamino)-3,4-dihydropyrimidin-4-one)
as
potential inhibitors against DHAD of MTB. The docking result
was verified by
molecular dynamics simulations. The inhibitors might be useful
for design of
drugs targeting BCAA biosynthesis.
Keywords:
BCAA Biosynthesis, DHAD,
tuberculosis, virtual screening, inhibitors