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Online Journal of Bioinformatics ©
Volume 13 (1):59-79, 2012.
Molecular modelling and docking of Brugia malayi glutathione reductase
Sudhanshu Shekhar Yadav1*, Vinay Kumar Singh2, Eva Liebau3, Sushma Rathaur1
1Department of Biochemistry, 2Centre for Bioinformatics, Faculty of Science, Banaras Hindu University, Varanasi 221005, U.P., India 3Westfalische Wilhelms-Uinversitat, Institute of Animal Physiology, Department of Molecular Physiology, Hindenburgplatz-55, Muenster, Germany
Yadav SS, Singh VK, Liebau E, Rathaur S., Molecular modelling and docking of Brugia malayi glutathione reductase, Online J Bioinform, 13 (1):59-79, 2012. Brugia malayi Glutathione Reductase (BmGR), a redox enzyme that reduces glutathione disulfide (GSSG) to the sulfhydryl form GSH plays an important role in filariasis and other diseases. BmGR was modeled using a 3DK9 template with 324 hydrogen Bonds, 18 helices, 32 strands and 47 turns and accepted at PMDB database (PM0077742). The model was used to dock and simulate the antifilarial drugs diethylcarbamazine citrate and albendazole, specific inhibitors of GR; 3,4 Dihydroxybenzyleamine and 1,3-bis(2-chloroethyl)-1-nitrosourea and substituted chalcones (SK series compounds). The active site analysis alignment of HsGR revealed ten stretches as active binding sites in BmGR. The amino acid residues SER19, GLU39, GLU40, THR41, THR46, TYR146, ASP162, ARG267, ARG272, ASP307 and THR315 were involved in hydrogen bonding, hydrophobic, polar, cation-pi and other interactions with NADPH. The binding of GSSG with protein especially with amino acids ALA142 and VAL143 and overlapped with NADPH binding site except SER19, ARG267, ARG272, ASP307 and THR315. In-silico investigation revealed that interaction of DEC with amino acids TYR181, ILE182 & ASP307 and SER19, THR46, ALA142, VAL143 & ALA318 interacting with ALB and specific inhibitors; DHBA showing interaction with amino acids GLU39, GLU40, THR41, THR46 & THR146 and SER19, GLY20 & THR46 with BCNU are involved in hydrogen, hydrophobic and polar level interactions. However, the interaction sites of antifilarials are similar to the binding sites of GSSG but positions are different and the binding sites of specific inhibitors are similar to the substrate i.e. active site domain II of BmGR protein. While SK series compounds are interact with highest coordination of the major portion of the active binding site as well as NADPH binding site of the protein. Based on estimated free energy of binding, lowest inhibition constant (Ki) and lower frequency percentage ALB, BCNU and substituted chalcones were showing better interactions. Specific inhibitors are showing competitive type binding (stretch 1 & 2) with substrate while substituted chalcones non-competitive (stretch 1, 2, 3 & 6). However, Stretch 5 and 7 may be the activator sites of the protein, which are the binding sites of antifilarials. Amino acids SER19, CYS47, CYS52 and PHE165 may be better inhibitory sites for drug designing using BmGR as template. Among substituted chalcone SK-3 and SK-5 are showing lower estimated free energy of binding, lowest inhibition constant (Ki) and lower frequency percentage. These substituted chalcones may be good inhibitors of glutathione metabolism and have better antifilarial activity. The BmGR structural information and docking studies could aid in screening new antifilarials or selective inhibitors for chemotherapy against filariasis.
Key Words: DEC; Diethylcarbamazine citrate, ALB; Albendazole, DHBA; 3,4 Dihydroxybenzyleamine, BCNU; 1,3-bis(2-chloroethyl)-1-nitrosourea, Substituted chalcones, filariasis.