Structure based virtual screening of novel inhibitors against multidrug resistant superbugs



Sinosh Skariyachan1*, Arpitha Badarinath Mahajanakatti1, 2, Narasimha Sharma1, 3, Shraddha Karanth1, 4, Shruthi Rao1, 5 & Narayanappa Rajeswari1



1R & D Center, Department of Biotechnology, Dayananda Sagar College of Engineering, Bangalore, India; 2Department of Bioinformatics, PES Institute of Technology, Bangalore, Karnataka, India; 3Infosys, Chennai, India; 4Department of Biotechnology Engineering, Lund University, SE-221 00 Lund, Sweden; 5Department of Genetic Engineering, SRM University, Chennai, India.


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Received April 27, 2012; Accepted April 30, 2012; Published May 15, 2012



Pathogenic microorganisms are persistently expressing resistance towards present generation antibiotics and are on the verge of joining the superbug family. Recent studies revealed that, notorious pathogens such as Salmonella typhi, Shigella dysenteriae and Vibrio cholerae have acquired multiple drug resistance and the treatment became a serious concern. This necessitates an alternative therapeutic solution. Present study investigates the utility of computer aided method to study the mechanism of receptor-ligand interactions and thereby inhibition of virulence factors (shiga toxin of Shigella dysenteriae, cholera toxin of Vibrio cholerae and hemolysin-E of Salmonella typhi) by novel phytoligands. The rational designs of improved therapeutics require the crystal structure for the drug targets. The structures of the virulent toxins were identified as probable drug targets. However, out of the three virulent factors, the structure for hemolysin-E is not yet available in its native form. Thus, we tried to model the structure by homology modeling using Modeller 9v9. After extensive literature survey, we selected 50 phytoligands based on their medicinal significance and drug likenesses. The receptor-ligands interactions between selected leads and toxins were studied by molecular docking using Auto Dock 4.0. We have identified two novel sesquiterpenes, Cadinane [(1S, 4S, 4aS, 6S, 8aS)- 4- Isopropyl- 1, 6-dimethyldecahydronaphthalene] and Cedrol [(8α)-Cedran-8-ol] against Shiga (binding energy -5.56 kcal/mol) and cholera toxins (binding energy -5.33 kcal/mol) respectively which have good inhibitory properties. Similarly, a natural Xanthophyll, Violaxanthin [3S, 3'S, 5R, 5'R, 6S, 6'S)-5, 5', 6, 6'-Tetrahydro-5, 6:5', 6'-diepoxy-β, β-carotene-3, 3'-diol] was identified as novel therapeutic lead for hemolysin-E (binding energy of 5.99 kcal/mol). This data provide an insight for populating the pool of novel inhibitors against various drug targets of superbugs when all current generation drugs seem to have failed.



Multiple drug resistance, Shiga toxin, Phytoligands, Drug likenesses, Sesquiterpenes, Superbugs



Skariyachan et al. Bioinformation 8(9): 420-425 (2012)

Edited by

P Kangueane






Biomedical Informatics



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