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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