Atherosclerosis is one of the top, multi-factorial diseases majorly responsible for the cause of deaths that makes the life-threatening clinical events such as acute coronary syndromes and stroke. Alongside, the widespread emergence of bacterial resistance to existing antibiotics has emphasized the need to develop novel therapeutics to treat atherosclerosis with the identification of new targets and novel therapeutics (Hema, 2015). The common offending organisms include Chlamydiophila pneumoniae, Poryphromonas gingivalis, Helicobacter pylori, Enterobacter hormaechei, Prevotella nigrescens, Prevotella intermedia, Streptococcus sanguinis, Tannerella forsythia, Aggregatibacter actinomycetemcomitans D11S-1, Aggregatibacter actinomycetemcomitans D7S-1 and Escherichia coli [Hema, 2015]. Over expression of human IL-6 drives the atherosclerosis disease progression hence, regarded as a prominent target in the present study to design novel antagonists (Fig. 1). Kalai et al., 2014 reported that inhibiting the binding affinity of human IL-6 and gp-130 effectively blocks the signaling pathway involved in atherosclerosis progression and also quoted that the residues Ile 29, Ile 32 and Leu 33 Arg 30, Arg 182 are majorly responsible for the binding of human IL-6 and gp-130 [Kalai, 1997]. The proposed lead 1 had good binding affinity, good docking scores and similar orientation with lead 1 were in well conformity with the binding orientation of gp-130 (Fig. 2). The additional five hydrogen bonds were formed with the binding site residues Tyr 31, Leu 33, Glu 110, Gln 111, Leu 178 and hydrogen bond with Lys 27 was observed in 98% of trajectories, Tyr 31 was observed in 96% and Arg 182 was observed with 79% trajectories strengthen the stability of lead 1 with human IL-6 with better binding affinity. The consistent energy, five water-mediated interactions, RMSD and RMSF of the complex was also within the limit (Fig. 3). Hence, the proposed lead can act as potential antagonists for inhibiting the human IL-6 in signaling pathway in the progression of atherosclerosis. The lead molecule would hold as a promising antagonist in drug discovery if synthesized and tested in animal models.

This research has been supported by DST-INSPIRE, Govt. of India, for the SRF. The authors are thankful to DBT, ministry of science and technology, Govt. of India for providing all facilities to carry out the work.

References

1. Hema K, Priyadarshini V, Pradhan D, Munikumar M, Sandeep S, Pradeep N, Suchitra MM, and Umamaheswari A (2015). Identification of putative drug targets and vaccine candidates for pathogens causing Atherosclerosis. Biochemistry & Analytical Biochemistry; 4: 1-9.

2. Hema, K.; Vani Priyadarshini, I.; Sandeep, S.; Pradeep, N.; Chiranjeevi, P.; Umamaheswari, A. Subunit vaccine design against pathogens causing atherosclerosis. J Biomol Struct Dyn. 2015, 33: supplement 1.

3. Kalai M, Montero-Julian FA, Grötzinger J, Fontaine V, Vandenbussche P, Deschuyteneer R, Wollmer A, Brailly H, Content J (1997). Analysis of the human interleukin-6/human interleukin-6 receptor binding interface at the amino acid level: proposed mechanism of interaction. Blood. 89:1319-1333.