Albany 2013: Book of Abstracts
June 11-15 2013
©Adenine Press (2012)
Discovery of potent KdsA inhibitors of Leptospira interrogans through homology modeling, docking and molecular dynamics simulations
Leptospira interrogans is the foremost cause of human leptospirosis. Discovery of novel lead molecules for common drug targets of more than 250 Leptospira serovars is of significant research interest. Lipopolysaccharide (LPS) layer prevent entry of hydrophobic agents into the cell and protect structural integrity of the bacterium. KDO-8-phosphate synthase (KdsA) catalyzes the first step of KDO biosynthesis that leads to formation of inner core of LPS. KdsA was identified as a potential drug target against Leptospira interrogans through subtractive genomic approach, metabolic pathway analysis and comparative analysis (Amineni et al., 2010). The present study rationalizes a systematic implementation of homology modeling, docking and molecular dynamics simulations to discover potent KdsA inhibitors (Pradhan et al, 2013; Umamaheswari et al., 2010). A reliable tertiary structure of KdsA in complex with substrate PEP was constructed based on co-crystal structure of Aquifex aeolicus KdsA synthase with PEP using Modeller9v10. Geometry based analog search for PEP was performed from LigandInfo database to generate an in house library of 352 ligands. The ligand dataset was docked into KdsA active site through three stage docking technique (HTVS, SP and XP) using Glidev5.7. Thirteen lead molecules were found to have better binding affinity compared to PEP (XP Gscore = -7.38 kcal/mol; Fig. 1). The best lead molecule (KdsA- lead1 docking complex) showed XP Gscore of -10.26 kcal/mol and the binding interactions (Fig. 2) were correlated favorably with PEP-KdsA interactions (Fig. 1). Molecular dynamics simulations of KdsA- lead1 docking complex for 10 ns had revealed that the complex (Fig. 3) remained stable in closer to physiological environmental condition. The predicted pharmacological properties of lead1 were well within the range of a drug molecule with good ADME profile, hence, would be intriguing towards development of potent inhibitor molecule against KdsA of Leptospira.
This research was supported by DBT, Ministry of Science & Technology, BIF program, Govt. of India (No. BT/BI/25/001/2006).
D. Pradhan D., Priyadarshini V., Munikumar M., Swargam S., Umamaheswari, A., & Aparna, B. (2013) Para-(benzoyl)-phenylalanine as a potential inhibitor against LpxC of Leptospira spp.: Homology modeling, docking and molecular dynamics study. J Biomol Struct Dyn (In Press), http://dx.doi.org/10.1080/07391102.2012.758056
A. Umamaheswari, A., Pradhan, D., & Hemanthkumar, M. (2010). Identification of potential Leptospira phosphoheptose isomerase inhibitors through virtual high-throughput screening. Genomics Proteomics Bioinformatics 8, 246–255.