Albany 2013: Book of Abstracts

category image Albany 2013
Conversation 18
June 11-15 2013
©Adenine Press (2012)

Structure based virtual screening towards identification of potential FabH inhibitors

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 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 (Fig. 1). An in-house library consisting of 23969 structural analogs from 60 available FabH inhibitors were 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 had revealed that the complex (Fig. 3) remained structurally and energetically stable in all 2084 trajectories. The docking interactions were also 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).


    V. Priyadarshini, V., Pradhan D, Munikumar M, Swargam S, Umamaheswari A & Rajasekhar D. (2013) In silico drug targets for infective endocarditis, Online J Bioinform14, 32‐50.

    V. Priyadarshini, V., Pradhan D, Munikumar M, Umamaheswari A, Rajasekhar D, et al. (2011) Docking and molecular dynamic simulations of Legionella pneumophila MurB reductase for potential inhibitor design. Biochem & Anal Biochem 1, 101.

Vani Priyadarshini
Dibyabhaba Pradhan
Manne Munikumar
Sandeep Swargam
Amineni Umamaheswari

Bioinformatics Centre, Department of Bioinformatics
Sri Venkateswara Institute of Medical Sciences University
Tirupati, Andhra Pradesh – 517507 India

Ph: +91-877-2287727