Journal of Biomolecular Structure and Dynamics
ISSN: 0739-1102 (Print) 1538-0254 (Online) Journal homepage: http://www.tandfonline.com/loi/tbsd20
176 Structure-based virtual screening towards identification of potential FabH inhibitors Vani Priyadarshini , Dibyabhaba Pradhan , Manne Munikumar , Sandeep Swargam & Amineni Umamaheswari To cite this article: Vani Priyadarshini , Dibyabhaba Pradhan , Manne Munikumar , Sandeep Swargam & Amineni Umamaheswari (2013) 176 Structure-based virtual screening towards identification of potential FabH inhibitors, Journal of Biomolecular Structure and Dynamics, 31:sup1, 113-114, DOI: 10.1080/07391102.2013.786418 To link to this article: http://dx.doi.org/10.1080/07391102.2013.786418
Published online: 29 May 2013.
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Book of Abstracts. Albany 2013: The 18th Conversation affinity against METH and AMP. Two mutants showed enhanced binding affinity for METH: scFv-I37 M by 1.3-fold and scFv-S93T by 2.6-fold. Additionally, all the mutants showed increase in affinity for AMP: scFvI37 M by 56-fold, scFv-S93T by 17-fold and scFvY34 M by 5-fold. Crystal structure for one of the high-affinity mutant, scFv-S93T, in complex with METH was determined (Figure 1). Binding pocket of the mutant is more hydrophobic in comparison with the wild type. ScFv6H4 binds METH in a deep pocket containing two water molecules. The substitution of a serine residue by a threonine leads to the expulsion of a water molecule (Figure 2), relieving some unfavorable contacts between the hydrocarbon atoms of METH and the water molecule and increasing the affinity to sub-nanomolar range.
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Structure-based virtual screening towards identification of potential FabH inhibitors
Vani Priyadarshini, Dibyabhaba Pradhan, Manne Munikumar, Sandeep Swargam and Amineni Umamaheswari* Bioinformatics Centre, Department of Bioinformatics, Sri Venkateswara Institute of Medical Sciences University, Tirupati, Andhra Pradesh 517507, India *Email:
[email protected], Phone: +91-877-2287727
Infective endocarditis (IE) is a serious form of microbial infection of the endocardial surface, lining of the heart chambers and heart valves with a high mortality rate. Through comparative genomics, subtractive genomics, and metabolic pathway analysis, 18 common drug targets were identified (Priyadarshini et al., 2013). In the present study, β-Ketoacyl-acyl carrier protein synthase III (FabH), a common protein among eight selected pathogens of IE, was selected for the study. FabH catalyzes the initiation of fatty acid elongation by condensing malonyl-ACP with acetyl-CoA. FabH is an
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Therefore, the present study shows that efficacy could be enhanced by altering the hydrophobicity or the shape of the binding pocket. References Celikel, R., Peterson, E. C., Owens, S. M., & Varughese, K. I. (2009). Crystal structures of a therapeutic single chain antibody in complex with two drugs of abuse-Methamphetamine and 3,4-methylenedioxymethamphetamine. Protein Science, 09, 2336–2345. Peterson, E. C., Laurenzana, E. M., Atchley, W. T., Hendrickson, H. P., & Owens, S. M. (2008). Development and preclinical testing of a high-affinity single-chain antibody against (+)methamphetamine. Journal of Pharmacology and Experimental Therapeutics, 08, 124–133.
essential enzyme for bacterial viability, because of its pivotal roles in both initiation and regulation of the fatty acid biosynthesis. Experimentally determined tertiary structure of FabH of Streptococcus mitis (reference organism) was not reported yet. Therefore, molecular modeling of FabH in complex with 2-({[4-bromo-3(diethylsulfamoyl) phenyl] carbonyl} amino) benzoic acid (B82) was constructed using Modeller9v10 (Figure 1). An in-house library consisting of 23969 structural analogs from 60 available FabH inhibitors was compiled from Ligand.Info database. Structure-based virtual screening was performed through three-stage docking technique (HTVS, SP, and XP) using Glide v5.7 led to identification of seven lead molecules with better binding affinity compared to published inhibitor (XP Gscore 8.268 kcal/mol). Lead1 showed the lowest XP Gscore of 9.953 kcal/mol with strong binding interactions with FabH. Molecular dynamic (MD) simulations (Priyadarshini et al., 2011) for FabH–lead1 docking complex were performed using Desmond v3.0 for 10 ns. It revealed that the complex (Figure 1) remained structurally and energetically stable in all 2084 trajectories. The docking interactions were also
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Journal of Biomolecular Structure and Dynamics Vol. 31, Supplement, 2013
reproduced during MD simulations. Therefore, lead1 would be a potent inhibitor of FabH and ideal for designing drug for IE. VP is highly thankful to ICMR, Ministry of Health & Family Welfare, Govt. of India, for sanctioning senior research fellowship (No. 45/18/2011-BIF/BMS). Authors are thankful to DBT, Ministry of Science & Technology, Govt. of India, for providing infrastructure through BIF program (No. BT/BI/25/001/2006).
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T-cell vaccine design for Streptococcus pneumoniae: an in silico approach
Manne Munikumar, Vani Priyadarshini, Dibyabhaba Pradhan, Sandeep Swargam and Amineni Umamaheswari* Bioinformatics Centre, Department of Bioinformatics, Sri Venkateswara Institute of Medical Sciences University, Tirupati 517507, Andhra Pradesh, India *Email:
[email protected], Phone: +91-877-2287727
Streptococcus pneumoniae (pneumococcus) remains an important cause of meningitis, bacteremia, acute otitis media, community acquired pneumonia associated with significant morbidity, and mortality world wide. Conjugated polysaccharide, glycoconjugated, and capsular polysaccharide based vaccines were existent for pneumococcal disease but are still specific and restricted
References Priyadarshini, V., Pradhan, D., Munikumar, M., Swargam, S., Umamaheswari, A., & Rajasekhar, D. (2011). Docking and molecular dynamic simulations of Legionella pneumophila MurB reductase for potential inhibitor design. Biochemistry and Analytical Biochemistry, 1, 101. Priyadarshini, V., Pradhan, D., Munikumar, M., Swargam, S., Umamaheswari, A., & Rajasekhar, D. (2013). In silico drug targets for infective endocarditis. Online Journal of Bioinformatics, 14, 32–50.
to serotypes of S. pneumoniae. Proteome of eight serotypes of S. pneumoniae was retrieved and identified in common proteins (Munikumar et al., 2012). 18 membrane proteins were distinguished from 1657 common proteins of eight serotypes of S. pneumoniae. Implementing comparative genomic approach and subtractive genomic approach, three membrane proteins were predicted as essential for bacterial survival and nonhomologous to human (Munikumar et al., 2012; Umamaheswari et al., 2011). ProPred server was used to propose four promiscuous T-cell epitopes from three membrane proteins and validated through published positive control, SYFPEITHI and immune epitope database (Munikumar et al., in press). The four epitopes docked into peptide binding region of predominant HLA-DRB alleles with good binding affinity in Maestro v9.2. The T-cell epitope 89-VVYLLPILI-97 and HLA-DRB5⁄0101 docking complex was with best XPG score ( 13.143 kcal/mol). Further, the stability of the complex was checked through