Sunday , 6 December 2020

An Insilico design of Inhibitors of GspB, a virulence factor of Streptococcus gordonii in the causation of infective Endocarditis

About author
Kannan I*, Iswarya K, Sambandam Cecilia, Jayalakshmi M, Premavathy RK, Shantha S
Department of Microbiology,
Tagore Dental College and Hospital, Rathinamangalam, Chennai – 600 127, India
E-mail: kannan_iyan@hotmail.com

Abstract
Infective endocarditis is an infection of the endocardial surface of the heart. The disease may be fatal if untreated as the disease may lead to intractable congestive heart failure and myocardial abscesses. Among the members of the viridans group, Streptococcus gordonii is a leading cause of infective endocarditis. Platelet binding by S. gordonii is predominantly mediated by the cell surface glycoprotein GspB. The S. gordonii defective in the production of GspB is found to lose its ability to bind to the platelets. Thus the production of GspB inhibitors can be an effective drug in the prevention of infective endocarditis caused by S. gordonii. The three dimensional structure of GspB was retrieved from RCSB database. The possible binding sites of GspB were searched using binding site prediction online tool Q site finder. A total of 1000 ligands were generated with the help of software ACD chemsketch. Rapid virtual screenings of these compounds were performed in the docking tool iGEMDOCK v2.0. Based on the binding energy a total of six ligands were selected for the further study. The selected six ligands were then analyzed for drug- relevant properties based on “Lipinski’s rule of five” and other drug like properties. The accurate docking of six ligands were performed using docking tool iGEMDOCK v2.0. From the present study, it has been found that (4-carbamoyl-5-hydroxy-6-iodo-1λ3-iodinin-2-yl) sodium, which is a novel compound can act has an inhibitor for the GspB.
Key words: Streptococcus gordonii, infective endocarditis, GspB inhibitors, molecular docking.
Introduction
Infective endocarditis is an infection of the endocardial surface of the heart. The disease may be fatal if untreated as the disease may lead to intractable congestive heart failure and myocardial abscesses. 
In association with prior injury or disease of the heart valves, the endothelial or exposed connective tissue surface becomes coated with platelets and fibrin, i.e., non-bacterial thrombotic vegetation . The thrombotic vegetation contains platelets which facilitates the binding of bacteria. The platelets on the surfaces of damaged cardiac valves provide an attachment site for bacteria that is circulated in the blood. This event is followed by the further accumulation of platelets at the site of infection. At least 50% of all human cases of infective endocarditis result from viridans group of streptococci [5]. The propensity of these organisms to produce endovascular infection may be attributable in part to their ability to bind platelets [6]. Among the members of the viridans group, Streptococcus gordonii is a leading cause of infective endocarditis. Platelet binding by S. gordonii is predominantly mediated by the cell surface glycoprotein GspB [8]. The 9.2-kb gspB gene encodes a protein of 3,072 amino acids, with a predicted molecular mass of 286 kDa. GspB is a serine-rich repeat (SRR) adhesin of S. gordonii that mediates binding of this organism to human platelets via its interaction with sialyl-T antigen on the receptor glycoprotein Ib alpha. This interaction appears to be a major virulence determinant in the pathogenesis of infective endocarditis .  The S. gordonii defective in the production of GspB is found to lose its ability to bind to the platelets. Thus the production of GspB inhibitors can be an effective drug in the prevention of infective endocarditis caused by S. gordonii. In the present study an attempt has been made to design an effective inhibitor of GspB by structure based drug design followed by molecular docking studies.

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