Tuberculosis (TB) is a bacterial infectious disease caused by the obligate human pathogen, Mycobacterium tuberculosis. Multidrug-resistant tuberculosis (MDR-TB) is a global reality that threatens tuberculosis control. Resistance to antibiotic Rifampicin, occurs in 95% of cases through nucleotide substitutions in an 81-bp core region of the rpoB i.e; beta subunit of DNA dependant RNA polymerase. In this paper, we studied the Rifampicin-rpoB receptor interactions In silico. First, homology modeling was performed to obtain the three dimensional structure of Mycobacterium rpoB. Sixty analogs of Rifampicin were prepared using Marvin sketch software. Both original Rifampicin and the analogs were docked with rpoB and energy values were obtained. Out of sixty analogs, 43 analogs had lesser energy values than conventional Rifampicin and hence are predicted to have greater binding affinity to rpoB. Thus, this study offers a route for the development of Rifampicin analogs against multi drug resistant Mycobacterium rpoB.
[1] R. Johnson, E.M. Streicher, G.E. Louw, R.M. Warren, P.D. Helden and
T.C.Victor, "Drug Resistance in Mycobacterium tuberculosis" in Curr.
Issues Mol. Biol.2006, 8: pp 97-112.
[2] M. Lipsitch and B.R. Levin, " Population dynamics of tuberculosis
treatment: mathematical models of the roles of non-compliance and
bacterial heterogeneity in the evolution of drug resistance, in Int. J.
Tuberc. Lung Dis. 1998, 2:pp 187-199.
[3] C.N. Paramasivan and P. Venkataraman, "Drug resistance in
tuberculosis in India", Review Article in Indian J. Med. Res. 2004, 120:
pp377-386.
[4] F.A. Drobniewski and S.M. Wilson, "The rapid diagnosis of isoniazid
and rifampin resistance in Mycobacterium tuberculosis: a molecular
story" in J.Med. Microbiol. 1998 47:pp189-196.
[5] A. Somoskovi, L.M. Parsons and M. Salfinger, "The molecular basis of
resistance to isoniazid, rifampin, and pyrazinamide in Mycobacterium
tuberculosis", Review Article in Respiratory Research 2001, 2 (3) :pp
164-168.
[6] W. Wehrli, "Rifampin:Mechanisms Of Action And Resistance", in Clin
Infect.Dis.1983, 5(3): pp S407-S411.
[7] S. Ramaswamy and J.M. Musser, " Molecular genetic basis of
antimicrobial agent resistance in Mycobacterium tuberculosis: 1998
update", in Tuberc. Lung Dis. 1998, 79:pp 3-29.
[8] E.A. Campbell , N. Korzheva ., A. Mustaev, K. Murakami , S. Nair, A.
Goldfarb and S.A. Darst S.A., " Structural Mechanism for Rifampicin
nhibition of Bacterial RNA polymerase", in Cell 2001, 104:pp 901-912.
[9] S.T. Cole, R. Brosch, J. Parkhill, T. Garnier, C. Churcher, D. Harris ,
S.V. Gordon, K. Eiglmeier, S. Gas and C.E. Barry, " Deciphering the
biology of Mycobacterium tuberculosis from the complete genome
sequence," in Nature 1998, 393: pp 537-544.
[10] L. Kant, "Translational Research In Tuberculosis: Bridging The Long
Journey From Bench To Bedside", in The Indian Journal Of
Tuberculosis 2005, 52:pp117- 119.
[11] H.M. Berman , J. Westbrook, Z. Feng, G. Gilliland, T.N. Bhat, H.
Weissig, I.N. Shindyalov and P.E. Bourne, "The Protein Data Bank", in
Nucleic Acids Research, 2000, 28: pp 235-242.
[12] S.F Altschul , W.Gish , W. Miller, E.W. Myers and D.J. Lipman ,
"Basic local alignment search tool", in J. Mol. Biol. 1990,215:pp 403-
410.
[13] S.F. Altschul, T.L Madden, A.A. Schaffer, J. Zhang, Z. Zhang,
W.Miller and D.J. Lipman, "Gapped BLAST and PSI-BLAST: a new
generation of protein database search programs", in Nucleic Acids Res.
1997, 50: pp3389-3402.
[14] D.J. Lipman, S.F. Altschul and J.D. Kececioglu, " A tool for multiple
sequence alignment", in Proc Natl Acad Sci U S A, 1989, 86(12):pp
4412-4415.
[15] R. Chenna, H. Sugawara , T. Koike, R. Lopez , T.J. Gibson , D.G.
Higgins J.D.Thompson, "Multiple sequence alignment with the Clustal
series of programs", in Nucleic Acids Res. 2003, 31 (13): pp3497-
3500.
[16] F. Sievers, A. Wilm , D.G. Dineen , T.J. Gibson, K. Karplus, W.Li,
R.Lopez, H. McWilliam, M. Remmert, J. Söding , J.D. Thompson and
D.G.Higgins, "Fast, scalable generation of high-quality protein multiple
sequence alignments using Clustal Omega", in Mol Syst Biol 2011,
pp77:539.
[17] S.B. Needleman and C.D. Wunsch, "A general method applicable to the
search for similarities in the amino acid sequence of two proteins",
Journal of Molecular Biology, 1970, 48 (3): pp443-53.
[18] N.Guex and M.C. Peitsch, "SWISS-MODEL and the Swiss-
PdbViewer:an environment for comparative protein modeling.", in
Electrophoresis, 1997, 18: pp2714-2723.
[19] C.O.Pardo , A. Cordero, J.R. Martinez and S. Imperial, "Homology
modeling of M. tuberculosis 2C-methyl-D-erythritol-4- phosphate
cytidylyltransferase, the third enzyme of the MEP pathway for
isoprenoid biosynthesis, Journal of Molecular Modelling,2009, pp 1-45.
[20] R.A.Laskoswki , M.W. MacArthur , D.S. Moss and J.M.Thornton,
"PROCHECK: a program to check the stereo chemical quality of protein
structures", J. Appl. Cryst.,1993, 26:pp283-291.
[21] S.P. Nataraj , P.B. KaviKishor, V.C.K. Reddy, P.E. Kumar, A.Anitha,
R.M.Kumar and R.L.Ananda, "Comparative Modeling and Docking
Studies of Mycobacterium tuberculosis H37RV rpoB Protein", in
Internet Electronic Journal of Molecular Design, 2008, 7: pp12-29.
[22] M.A.Bauer, S. Lu , J.B. Anderson, F. Chitsaz , M.K. Derbyshire, C. De
Wesse-Scott, J.H. Fong , L.Y. Geer , R.C. Geer , N.R. Gonzales , M.
Gwadz , D.I. Hurwitz , J.D. Jackson, Z. Ke , C.J. Lanczycki, F. Lu, G.H.
Marchler, M. Mullokandov, M.V. Omelchenko, C.L. Robertson, J.S.
Song., N. Thanki., R.A. Yamashita, D.Zhang., N. Zhang ., C.Zheng.,
S.H. Bryant , "CDD: a Conserved Domain Database for the functional
annotation of proteins. Nucleic Acids Research, 2011, 39:pp 225-229.
[23] A User Guide for Marvin Sketch from www.chemaxon.com.
[24] D.W.Ritchie and G.J.L.Keg, "Protein Docking Using Spherical Polar
Fourier Correlations",in Proteins:Struct.Funct.Genet., 2000,39:pp94-
178.
[25] D.W.Ritchie, "Hex 6.3 User Manual Protein Docking Using Spherical
Polar Fourier Correlations", Copyright 1996-2010.
[26] U,H. Patel, R.A.Barot, B.D.Patel , D.A.Shah and R.D. Modh," Docking
studies of pyrrole derivatives using Hex", in International Journal of
Environmental Sciences, 2012, 2(3):pp 1765-1770.
[27] K.S. Murakami , S. Masuda and S.A. Darst, "Structural basis of
transcription initiation:RNA polymerase holoenzyme at 4 A0 resolution"
, in Science,2002, 296(5571):pp 1280-4.
[28] C.I├▒aki, J. Chakravartti, P.M. Small, J. S. Galagan, K.Kremer, J.D.Ernst
and S.Gagneux, "Human T cell epitopes of Mycobacterium
tuberculosisare evolutionarily hyperconserved", in Nature
Genetics,2010. 42:498- 503.
[29] S.B.Silverman, "The Organic Chemistry of Drug Design and Drug
Action,Chapter 2: Drug Discovery, Design And Development, Section
2.2: Lead Modification", Edition 2,2004 :pp 18-34.
[1] R. Johnson, E.M. Streicher, G.E. Louw, R.M. Warren, P.D. Helden and
T.C.Victor, "Drug Resistance in Mycobacterium tuberculosis" in Curr.
Issues Mol. Biol.2006, 8: pp 97-112.
[2] M. Lipsitch and B.R. Levin, " Population dynamics of tuberculosis
treatment: mathematical models of the roles of non-compliance and
bacterial heterogeneity in the evolution of drug resistance, in Int. J.
Tuberc. Lung Dis. 1998, 2:pp 187-199.
[3] C.N. Paramasivan and P. Venkataraman, "Drug resistance in
tuberculosis in India", Review Article in Indian J. Med. Res. 2004, 120:
pp377-386.
[4] F.A. Drobniewski and S.M. Wilson, "The rapid diagnosis of isoniazid
and rifampin resistance in Mycobacterium tuberculosis: a molecular
story" in J.Med. Microbiol. 1998 47:pp189-196.
[5] A. Somoskovi, L.M. Parsons and M. Salfinger, "The molecular basis of
resistance to isoniazid, rifampin, and pyrazinamide in Mycobacterium
tuberculosis", Review Article in Respiratory Research 2001, 2 (3) :pp
164-168.
[6] W. Wehrli, "Rifampin:Mechanisms Of Action And Resistance", in Clin
Infect.Dis.1983, 5(3): pp S407-S411.
[7] S. Ramaswamy and J.M. Musser, " Molecular genetic basis of
antimicrobial agent resistance in Mycobacterium tuberculosis: 1998
update", in Tuberc. Lung Dis. 1998, 79:pp 3-29.
[8] E.A. Campbell , N. Korzheva ., A. Mustaev, K. Murakami , S. Nair, A.
Goldfarb and S.A. Darst S.A., " Structural Mechanism for Rifampicin
nhibition of Bacterial RNA polymerase", in Cell 2001, 104:pp 901-912.
[9] S.T. Cole, R. Brosch, J. Parkhill, T. Garnier, C. Churcher, D. Harris ,
S.V. Gordon, K. Eiglmeier, S. Gas and C.E. Barry, " Deciphering the
biology of Mycobacterium tuberculosis from the complete genome
sequence," in Nature 1998, 393: pp 537-544.
[10] L. Kant, "Translational Research In Tuberculosis: Bridging The Long
Journey From Bench To Bedside", in The Indian Journal Of
Tuberculosis 2005, 52:pp117- 119.
[11] H.M. Berman , J. Westbrook, Z. Feng, G. Gilliland, T.N. Bhat, H.
Weissig, I.N. Shindyalov and P.E. Bourne, "The Protein Data Bank", in
Nucleic Acids Research, 2000, 28: pp 235-242.
[12] S.F Altschul , W.Gish , W. Miller, E.W. Myers and D.J. Lipman ,
"Basic local alignment search tool", in J. Mol. Biol. 1990,215:pp 403-
410.
[13] S.F. Altschul, T.L Madden, A.A. Schaffer, J. Zhang, Z. Zhang,
W.Miller and D.J. Lipman, "Gapped BLAST and PSI-BLAST: a new
generation of protein database search programs", in Nucleic Acids Res.
1997, 50: pp3389-3402.
[14] D.J. Lipman, S.F. Altschul and J.D. Kececioglu, " A tool for multiple
sequence alignment", in Proc Natl Acad Sci U S A, 1989, 86(12):pp
4412-4415.
[15] R. Chenna, H. Sugawara , T. Koike, R. Lopez , T.J. Gibson , D.G.
Higgins J.D.Thompson, "Multiple sequence alignment with the Clustal
series of programs", in Nucleic Acids Res. 2003, 31 (13): pp3497-
3500.
[16] F. Sievers, A. Wilm , D.G. Dineen , T.J. Gibson, K. Karplus, W.Li,
R.Lopez, H. McWilliam, M. Remmert, J. Söding , J.D. Thompson and
D.G.Higgins, "Fast, scalable generation of high-quality protein multiple
sequence alignments using Clustal Omega", in Mol Syst Biol 2011,
pp77:539.
[17] S.B. Needleman and C.D. Wunsch, "A general method applicable to the
search for similarities in the amino acid sequence of two proteins",
Journal of Molecular Biology, 1970, 48 (3): pp443-53.
[18] N.Guex and M.C. Peitsch, "SWISS-MODEL and the Swiss-
PdbViewer:an environment for comparative protein modeling.", in
Electrophoresis, 1997, 18: pp2714-2723.
[19] C.O.Pardo , A. Cordero, J.R. Martinez and S. Imperial, "Homology
modeling of M. tuberculosis 2C-methyl-D-erythritol-4- phosphate
cytidylyltransferase, the third enzyme of the MEP pathway for
isoprenoid biosynthesis, Journal of Molecular Modelling,2009, pp 1-45.
[20] R.A.Laskoswki , M.W. MacArthur , D.S. Moss and J.M.Thornton,
"PROCHECK: a program to check the stereo chemical quality of protein
structures", J. Appl. Cryst.,1993, 26:pp283-291.
[21] S.P. Nataraj , P.B. KaviKishor, V.C.K. Reddy, P.E. Kumar, A.Anitha,
R.M.Kumar and R.L.Ananda, "Comparative Modeling and Docking
Studies of Mycobacterium tuberculosis H37RV rpoB Protein", in
Internet Electronic Journal of Molecular Design, 2008, 7: pp12-29.
[22] M.A.Bauer, S. Lu , J.B. Anderson, F. Chitsaz , M.K. Derbyshire, C. De
Wesse-Scott, J.H. Fong , L.Y. Geer , R.C. Geer , N.R. Gonzales , M.
Gwadz , D.I. Hurwitz , J.D. Jackson, Z. Ke , C.J. Lanczycki, F. Lu, G.H.
Marchler, M. Mullokandov, M.V. Omelchenko, C.L. Robertson, J.S.
Song., N. Thanki., R.A. Yamashita, D.Zhang., N. Zhang ., C.Zheng.,
S.H. Bryant , "CDD: a Conserved Domain Database for the functional
annotation of proteins. Nucleic Acids Research, 2011, 39:pp 225-229.
[23] A User Guide for Marvin Sketch from www.chemaxon.com.
[24] D.W.Ritchie and G.J.L.Keg, "Protein Docking Using Spherical Polar
Fourier Correlations",in Proteins:Struct.Funct.Genet., 2000,39:pp94-
178.
[25] D.W.Ritchie, "Hex 6.3 User Manual Protein Docking Using Spherical
Polar Fourier Correlations", Copyright 1996-2010.
[26] U,H. Patel, R.A.Barot, B.D.Patel , D.A.Shah and R.D. Modh," Docking
studies of pyrrole derivatives using Hex", in International Journal of
Environmental Sciences, 2012, 2(3):pp 1765-1770.
[27] K.S. Murakami , S. Masuda and S.A. Darst, "Structural basis of
transcription initiation:RNA polymerase holoenzyme at 4 A0 resolution"
, in Science,2002, 296(5571):pp 1280-4.
[28] C.I├▒aki, J. Chakravartti, P.M. Small, J. S. Galagan, K.Kremer, J.D.Ernst
and S.Gagneux, "Human T cell epitopes of Mycobacterium
tuberculosisare evolutionarily hyperconserved", in Nature
Genetics,2010. 42:498- 503.
[29] S.B.Silverman, "The Organic Chemistry of Drug Design and Drug
Action,Chapter 2: Drug Discovery, Design And Development, Section
2.2: Lead Modification", Edition 2,2004 :pp 18-34.
@article{"International Journal of Biological, Life and Agricultural Sciences:61735", author = "Virupakshaiah DBM and Madiha Ahmed and Smita T. Patil and Chandrakanth Kelmani", title = "Molecular Docking Studies of Mycobacterium tuberculosis RNA Polymerase β Subunit (rpoB) Receptor", abstract = "Tuberculosis (TB) is a bacterial infectious disease caused by the obligate human pathogen, Mycobacterium tuberculosis. Multidrug-resistant tuberculosis (MDR-TB) is a global reality that threatens tuberculosis control. Resistance to antibiotic Rifampicin, occurs in 95% of cases through nucleotide substitutions in an 81-bp core region of the rpoB i.e; beta subunit of DNA dependant RNA polymerase. In this paper, we studied the Rifampicin-rpoB receptor interactions In silico. First, homology modeling was performed to obtain the three dimensional structure of Mycobacterium rpoB. Sixty analogs of Rifampicin were prepared using Marvin sketch software. Both original Rifampicin and the analogs were docked with rpoB and energy values were obtained. Out of sixty analogs, 43 analogs had lesser energy values than conventional Rifampicin and hence are predicted to have greater binding affinity to rpoB. Thus, this study offers a route for the development of Rifampicin analogs against multi drug resistant Mycobacterium rpoB.", keywords = "Marvin Sketch, Mycobacterium tuberculosis,Rifampicin, rpoB.", volume = "7", number = "5", pages = "317-6", }
