Abstract
AbstractThe incidence of infective endocarditis (IE) represents the fourth leading cause of life-threatening infectious disease with a yearly incidence of 15,000 to 20,000 new cases despite advances in antimicrobial therapy, development of better diagnostic and surgical techniques. The diverse group of causative microbes of IE is one of major obstacle towards development of effective antimicrobial drug. This has triggered exploration of common potential novel drug target from available whole genome sequences of predominant pathogens causing IE in SVIMS hospital through comparative subtractive genomic approach and metabolic pathway analysis. Streptococcus mitis is the most predominant IE pathogen in SVIMS hospital. Thymidylate kinase of Streptococcus mitis plays a vital role in pyrimidine metabolism in deoxyribonucleic acid (DNA) synthesis was identified as novel common drug target against IE. Computational tools were utilized further to gain insight on physico-chemical, structural and functional aspects of the protein for facilitating structure based drug design for discovery of novel drug molecule. Motifs and domains of thymidylate kinase were predicted. Secondary structural elements were predicted using NPS server and PROTEUS server. Three dimensional model of thymidylate kinase was constructed based on thymidylate kinase (2CCJ) of Staphylococcus aureus as template using Modeller9v7. DOPE score correlation, PROCHECK, ProSA and superpose results confirmed the predicted model is of good quality. The active site residues of thymidylate kinase were derived by incorporating natural substrate into predicted model from the template. Further, the active site was validated through multiple sequence alignment and CASTp analysis. The 3D model with predicted active site will aid in designing drug against organisms causing infective endocarditis.
Highlights
Streptococcus mitis NCTC 12261, Enterococcus faecalis V583 and Staphylococcus aureus subsp aur JH9 were identified as three predominant pathogens in infective endocarditis (IE) patients of SVIMS hospital and explored for common novel drug targets from available whole genome sequences through comparative genomic approach, subtractive genomic approach and metabolic pathway analysis
Thymidylate kinase plays a vital role in pyrimidine metabolism in deoxyribonucleic acid (DNA) synthesis and was identified as novel common potential drug target against IE
Active site of modeled thymidylate kinase was determined for assisting structure based drug discovery
Summary
SVIMS Bioinformatics centre, SVIMS university, Tirupati, PIN-517307, Andhra Pradesh, India. Streptococcus, Enterococcus, Legionella, Staphylococcus, Brucella, tropheryma, Coxiella, Bortonella, Nocardia, Chlamidia, Neisseria, HACEK and Mycoplasma are the causative organisms of IE. Streptococcus mitis NCTC 12261, Enterococcus faecalis V583 and Staphylococcus aureus subsp aur JH9 were identified as three predominant pathogens in IE patients of SVIMS hospital and explored for common novel drug targets from available whole genome sequences through comparative genomic approach, subtractive genomic approach and metabolic pathway analysis.
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