Insilico drug designing and Lead Compound validation against YycG histidine kinase

Shama Najir-Ahemad Mujawar, Priyanka Parhi, Sameer Chaudhary


In bacteria, signal transduction in response to a wide variety of environmental stimuli is mediated by pairs of proteins that communicate with each other through a two-component signal transduction system (TCS) involving protein phosphorylation. TCS consists of a histidine kinase and a response regulator, which play global roles in bacterial growth as well as drug-resistance, virulence, biofilm formation, and regulation of receptors of plant hormones such as ethylene and cytokinine. TCSs are attractive antimicrobial targets considering various prospects. YycG/YycF which is highly conserved and specific to low G +C Gram positive bacteria, are essential for Bacillus subtilis and Staphylococcus aureus survival. Inhibitors of YycG histidine kinase, such as aranorosinol B, thiazolidinone, isothiazolone etc have been screened and documented against Bacillus subtilus. This prompted us to demonstrate that S. epidermidis possesses a homologous YycG/YycF TCS, and to investigate whether it would be an appropriate target for the design of novel antibacterial agents. In our study, these novel inhibitors ZINC00518229 (GLN299:HE22), ZINC0387112 (GLN229: HE22),  ZINC00014168 (HIS466:HD1),  ZINC13377075 (HIS466:HD1) of YycG histidine kinase show interaction with active site residues and  are considered as promising lead-compounds for developing new compounds against staphylococci infections.


Histidine Kinase, TCS, Drug Designing, YycG/YycF, Docking, Insilico Analysis


C. Fabret, J.A. Hoch. A two-component signal transduction system essential for growth of Bacillus subtilis: implications for anti-infective therapy. J. Bacteriol 1998; 180(): 6375–6383.

S. Dubrac, T. Msadek. Identification of genes controlled by the essential YycG/YycF two-component system of Staphylococcus aureus. J. Bacteriol 2004; 186(): 1175–1181.

J.A. Hoch, T.J. Silhavy. Two-component Regulatory Systems. ASM Press 1995; (): .

C.J. Bent, N.W. Isaacs, T.J. Mitchell, A. Riboldi-Tunnicliffe. Crystal structure of the response regulator 02 receiver domain, the essential YycF two-component system of Streptococcus pneumoniae in both complexed and native states. J. Bacteriol 2004; 186(): 2872–2879.

A.G. Blanco, M. Sola, F.X. Gomis-Ruth, M. Coll. Tandem DNA recognition by PhoB, a two-component signal transduction transcriptional activator, Structure. 2002; 10(): 701–713.

Galperin, M. Y. Structural classification of bacterial response regulators: diversity of output domains and domain combinations. J. Bacteriol 2006; 188(): 4169-4182.

Dutta, R., L. Qin, and M. Inouye. Histidine kinases: diversity of domain organization. Mol. Microbiol 1999; 34(): 633-640.

Grebe, T. W., and J. B. Stock. The histidine protein kinase superfamily. Adv. Microb. Physiol 1999; 41(): 139-227.

Monson, E. K., M. Weinstein, G. S. Ditta, and D. R. Helinski. The FixL protein of Rhizobium meliloti can be separated into a heme-binding oxygen-sensing domain and a functional C-terminal kinase domain. Proc. Natl. Acad. Sci. USA 1992; 89(): 4280-4284.

Karniol, B., and R. D. Vierstra. The HWE histidine kinases, a new family of bacterial two-component sensor kinases with potentially diverse roles in environmental signaling. J. Bacteriol 2004; 186(): 445-453.

Wolanin, P. M., P. A. Thomason, and J. B. Stock. Histidine protein kinases: key signal transducers outside the animal kingdom. Genome Biol 2002; 3(REVIEWS301): .

Fabret, C., and J. A. Hoch. A two-component signal transduction system essential for growth of Bacillus subtilis: implications for anti-infective therapy. J. Bacteriol 1998; 180(): 6375-6383.

Federle, M. J., K. S. McIver, and J. R. Scott. A response regulator that represses transcription of several virulence operons in the group A Streptococcus. J. Bacteriol 1999; 181(): 3649-3657.

Lange, R., C. Wagner, A. de Saizieu, N. Flint, J. Molnos, M. Stieger,et al. Domain organization and molecular characterization of 13 two-component systems identified by genome sequencing of Streptococcus pneumoniae. Gene 1999; 237(): 223-234.

Martin, P. K., T. Li, D. Sun, D. P. Biek, and M. B. Schmid. Role in cell permeability of an essential two-component system in Staphylococcus aureus. J. Bacteriol 1999; 181(): 3666-3673.).

Kallipolitis, B. H., and H. Ingmer. Listeria monocytogenes response regulators important for stress tolerance and pathogenesis. FEMS Microbiol. Lett 2001; 204(): 111-115. (accessed ).

Throup, J. P., K. K. Koretke, A. P. Bryant, K. A. Ingraham, A. F. Chalker, Y. Ge,et al. A genomic analysis of two-component signal transduction in Streptococcus pneumoniae. Mol. Microbiol 2000; 35(): 566-576.

Wagner, C., A. Saizieu Ad, H. J. Schonfeld, M. Kamber, R. Lange, C. J. Thompson,et al. Genetic analysis and functional characterization of the Streptococcus pneumoniae vic operon. Infect. Immun 2002; 70(): 6121-6128.

Schultz, J., F. Milpetz, P. Bork, and C. P. Ponting. SMART, a simple modular architecture research tool: identification of signaling domains. Proc. Natl. Acad. Sci. USA 1998; 95(): 5857-5864.

Taylor, B. L., and I. B. Zhulin. PAS domains: internal sensors of oxygen, redox potential, and light. Microbiol. Mol. Biol 1999; Rev. 63(): 479-506.

Koretke, K. K., A. N. Lupas, P. V. Warren, M. Rosenberg, and J. R. Brown. Evolution of two-component signal transduction. Mol. Biol. Evol 2000; 17(): 1956-1970.

Fabret, C., V. A. Feher, and J. A. Hoch. Two-component signal transduction in Bacillus subtilis: how one organism sees its world. J. Bacteriol 1999; 181(): 1975-1983.

Thompson JD, Gibson TJ, Plewniak F, Jeanmougin F, Higgins DG. The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res 1995; 25(24)(): 4876-4882.

Sali A, Blundell TL. Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 1993; 234(3)(): 779-815.

Zhiqiang Qin†1, Jian Zhang†2, Bin Xu1, Lili Chen2, Yang Wu1, Xiaomei Yang1, et al. Structure-based discovery of inhibitors of the YycG histidine kinase: New chemical leads to combat Staphylococcus epidermidis infections. BMC Microbiology 2006; 6(96): 1471-2180.

Takafumi watanable, Ariookada, Yasuhira gotoh, Ryutaro utsumi. . Chapter 16, Inhibitors Tragetting Two-component signal transduction, Bacterial Signal Transduction: Networks and drug targets; ():.

Raymond Gilmour, J. Estelle Foster, Qin Sheng, Jonathan R. McClain, Anna Riley,et al. New Class of Competitive Inhibitor of Bacterial Histidine Kinases. J Bacteriol Dec 2005; doi: 10.1128/JB.187.23(): 8196-8200.

Igarashi M, Watanabe T, Hashida T, Umekita M, Hatano M, Yanagida Y,et al. Waldiomycin, a novel WalK-histidine kinase inhibitor from Streptomyces sp. J Antibiot (Tokyo) 2013; 66(8)(): 459-64.

Ren-zheng Huang, Li-kang Zheng, Hua-yong Liu, Bin Pan, Jian Hu, Tao Zhu, et al. Thiazolidione derivatives targeting the histidine kinase YycG are effective against both planktonic and biofilm-associated Staphylococcus epidermidis, Acta Pharmacologica Sinica . 2011; 166(): 418–425.

Joe Dundas, Zheng Ouyang, Jeffery Tseng, Andrew Binkowski, Yaron Turpaz, and Jie Liang. CASTp: computed atlas of surface topography of proteins with structural and topographical mapping of functionally annotated resiudes. Nucleic Acid Research 2006; 34(): W116-W118.

Zengming Zhang, Yu Li, Biaoyang Lin, Michael Schroeder and Bingding Huang. Identification of cavities on protein surface using multiple computational approaches for drug binding site prediction. Bioinformatics 2011; 27 (15)(): 2083-2088.

David Ryan Koes and Carlos J. Camacho. ZINCPharmer: pharmacophore search of the ZINC database,. ; (): .

Irwin, Sterling, Mysinger, Bolstad and Coleman. The original publication is Irwin and Shoichet. J. Chem. Inf. Model 2005; 45(1) (): 177-82.

Oleg Trott and Arthur J. Olson. AutoDock Vina: Improving the speed and accuracy of docking with a new scoring function, efficient optimization, and multithreading. ; DOI: 10.1002/jcc.21334 ():.