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OJBTM
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
ABSTRACT
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.